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Department of Neuroscience (S.P.K., S.P., B.X.), Department of Physiology (M.G.D., P.S.K.), and The University of Florida Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32610; and Department of Obstetrics and Gynecology (T.L.H.), Yale University School of Medicine, New Haven, Connecticut 06510
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 Top Abstract I. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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-aminobutyric acid |
I. Introduction |
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TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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Consequently, information amassed during this decade has revised our views on the hypothalamic control of appetite and helped to detail the mechanistic attributes of locally derived signals in regulating energy homeostasis. These attributes have crystallized into the following broad categories: 1) Embedded in the networks controlling a multitude of hypothalamic functions (1, 13, 14), there is a distinct circuitry regulating appetite. This circuitry is composed of an interconnected network of pathways elaborating and emitting orexigenic and anorexigenic signals (1, 15). 2) The neurons producing these orexigenic and anorexigenic signal molecules are subject to modulation by the internal milieu comprised of a variety of hormonal and other biologically active molecules. In this respect, the recent identification of the adipocyte protein, leptin, has renewed interest in feedback mechanisms between adipocytes and the appetite-regulating hypothalamic circuitry (16, 17). 3) A cascade of temporally related neural events in various components of the appetite-regulating network (ARN) precedes feeding episodes. 4) Emerging evidence supports the involvement of a distinct neural device for the timely onset of appetite expression, and disintegration of this control may result in unregulated food consumption. 5) A deficit in availability of orexigenic signal(s) at the signal transduction level, whether temporary or permanent, can perturb the postsynaptic receptor dynamics that eventuate in hyperphagia and increased body weight gain indistinguishable from that produced by excessive production and release of orexigenic signals (1, 18, 19). 6) Coexistence and corelease of orexigenic signals (20, 21, 22), along with the redundant overlapping and interconnected orexigenic and anorexigenic signaling pathways within the hypothalamus (1, 12, 15, 23), provide a microenvironment wherein subtle perturbations shift signaling in favor of unregulated hyperphagia rather than anorexia. The central theme of this article is to critically review our understanding of these fundamentals underlying neural control of appetite and to collate the growing information on several newly identified messenger molecules. Emphasis is placed on the anatomical distribution of signal-producing pathways in the hypothalamus, the site and mode of action of peripheral signals, and the cellular and subcellular events underlying hyperphagia and obesity in experimental and genetic models. In doing so we will present a conceptual model, which encompasses a broad spectrum of appetite-regulating messenger molecules, to explain the dynamics of the neural circuitry involved in stimulation and inhibition of appetite.
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II. Neuroanatomical Substrate for Appetite Regulation |
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TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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Recent intensive research, first for identification of orexigenic and
anorexigenic neurotransmitters in the hypothalamus, followed by
identification of the neuronal sites of their production, release, and
receptive fields, has changed the landscape of the neuroanatomical
substrate underlying ingestive behavior. Also, evidence of the
morphological relationships among these
neurotransmitter/neuromodulator-producing neurons, and the fact that
these neurons can coproduce more than one appetite-regulating signal
(1, 13, 20, 21, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41), have strengthened the concept, enunciated
earlier (1, 12), that a distinct interconnected circuitry operates
locally in the hypothalamus to regulate ingestive behavior. The
following are the currently known anatomical components of this
hypothalamic circuitry (Fig. 1
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). It
extends rostrocaudally from the posterior borders of the optic chiasm
to the mamillary bodies. This nucleus has recently gained prominence
among the sites associated with the hypothalamic integration of energy
balance due to two reasons. It contains a high density of neurons that
produce the orexigenic peptides, NPY (21, 41), the opioids, dynorphin,
and the POMC-derived peptide, ß-endorphin [ß-END (42, 43, 44)],
galanin [GAL (45, 46)], and the amino acids, -aminobutyric acid
[GABA (47, 48)] and glutamate (49, 50). Interestingly, 
MSH, an
anorexigenic peptide derived from the POMC precursor protein, is also
coproduced with ß-END in the ARC (51, 52, 53). The agouti-related
transcript (ART) that encodes the anorectic agouti-related protein
(AgrP), the selective antagonist of MC3-R and MC4-R receptor subtypes
(54, 55), is coexpressed with NPY mRNA in the ARC (39, 40). The
terminal fields of these orexigenic and anorexigenic producing neurons
in the ARC extend into various hypothalamic sites including the VMN,
DMN, perifornical hypothalamus (PFH), PVN, and preoptic area (POA)
where microinjection of these neurotransmitters/neuromodulators affects
feeding behavior (see respective sections dealing with these signal
molecules). Morphological evidence has demonstrated that a subpopulation of neurons in the ARC coexpress NPY and GABA (36, 37, 38), and NPY-producing neurons are synaptically linked with ß-END- (34) and GAL-producing neurons in the ARC (33). Also, GAL-producing neurons establish morphological and functional links with ß-END-producing neurons within the ARC (35). Further, experimental evidence has demonstrated that an interconnected orexigenic network is likely to operate in the hypothalamic control of the daily patterning of food intake in which synergistic action of NPY and GABA (37, 38) and regulation of ß-END (34, 56) and GAL (35) release by NPY may play predominant roles. Recently, cocaine and amphetamine-regulated transcript (CART) mRNA has been localized in the ARC, and CART peptides appear to be physiologically relevant anorexigenic signals (57, 58, 59, 60, 61). In addition, due to the absence of blood brain barrier, the ARC is strategically positioned to be in direct communication with peripheral signals, such as the circulating adrenal and gonadal steroids as well as the large peptides, leptin and insulin, and the signals transported via the cerebrospinal fluid in the cerebroventricular system (14).
B. Ventromedial nucleus and lateral hypothalamus
Lesions in the ventromedial hypothalamus (VMH) that include the
ventromedial nucleus (VMN) produce rapid hyperphagia and abnormal body
weight gain that persist for a long time (24, 25, 26). The hypotheses that
VMN is a "satiety center" exercising constant restraint on feeding
and destruction of neuronal elements in the VMN permanently abolishes
this restraint to allow sustained, unregulated phagia have been
seriously contested over the years (13, 28, 29, 30). Evidence that
parasagittal transections of fibers, between the LH, a hunger center,
and the VMN extending up to the anterior hypothalamus, reproduced the
VMH lesion-type hyperphagia and obesity challenged the role of the VMN
in regulation of appetite (28, 30). However, in view of the emerging
knowledge of the existence of an ARN extending over several
hypothalamic sites, it is highly likely that the hyperphagia and
obesity produced by VMH lesions and by transections of discrete
pathways traversing the VMN are two distinct syndromes involving
disruptions in disparate pathways (18, 19, 62). For example,
microinjection of colchicine to disrupt neural signaling in the VMN
diminished the availability and release of NPY in the ARC-PVN but
augmented the galaninergic signaling in the hypothalamus (63, 64, 65, 66, 67). In
addition, NPY gene expression was induced in hypothalamic sites that
normally do not express NPY (68). Also, recent evidence clearly shows
that VMH lesions disrupt signaling differently in each of the
orexigenic pathways (see Section III.A.1 and Refs. 63, 64, 65, 66, 67, 68).
Although there is no evidence yet of production of either orexigenic or anorexigenic signals in the VMN, selective destruction of cell bodies in the VMN with ibotenic acid resulted in hyperphagia and increased rate of body weight gain (69) thus reemphasizing the role of neuronal elements in the VMN in regulation of appetite. On the other hand, microinjection into the VMN of NPY (13, 70), GAL (71, 72, 73), GABA, or GABA-agonist (74, 75, 76, 77) and ß-END (13, 74) stimulated feeding, while injections of leptin inhibited feeding (78, 79). Interestingly, microinjection of urocortin, a potent anorexigenic peptide, into the VMN also inhibited feeding (80). These findings raise the possibility of a receptive field in the VMN for several appetite-regulating signal molecules. The argument that spread of these signals through the extracellular fluid to receptive sites in the neighborhood most likely affected feeding is tenuous because receptors for each of these signals do exist in the VMN (see sections on each of these signals).
Further, the VMN is neurally linked with several hypothalamic sites implicated in the control of ingestive behavior. Although VMN efferents to the ARC have not been described, the VMN receives NPY (21), ß-END (43, 44), and CART (59, 61) containing projections from the ARC. VMN efferents to the DMN and parvocellular subdivision of the PVN (pPVN) have been traced, thereby supporting the possibility that disruption in signaling within the VMN may perturb flow of information to the DMN-PVN axis for the release of orexigenic signals, the consequence of which is unregulated feeding (81, 82, 83, 84).
LH is a contiguous band dorsal and lateral to VMH, extending rostrally from the mesencephalic tegmentum to the lateral preoptic area. In addition to sparsely distributed neuronal subpopulations, it is the site of passage for the medial forebrain bundle and other fibers connecting forebrain and midbrain structures with each other and several hypothalamic sites. Lesions in the LH produced temporary aphagia, adipsia, and loss in body weight (24, 25, 26, 27, 85). The severity of the LH syndrome and near normal recovery of food intake and body weight depended upon the location and the size of the lesion (85). These observations led Anand and Brobeck (24, 25) to conceptualize LH as a "feeding center" for elaboration of "urge to eat" normally restrained by signals from VMH. The fact that daily electrical stimulation of LH produced vigorous feeding leading to increase in body weight (86, 87) suggests the possibility that LH stimulation either restrained the action of an orexigenic signal(s) or activated those orexigenic pathways originating locally or in the vicinity of the LH. Indeed, recent evidence that melanin-concentrating hormone (MCH), orexins, and excitatory amino acid (EAA) glutamate are produced in the LH and microinjection of orexin and glutamate agonist stimulates feeding strengthen the view that LH is an integral part of the ARN in the forebrain (for details see Sections III.D, III.E, and III.F).
C. Dorsomedial nucleus
Electrolytic lesions in the dorsomedial nucleus (DMH) disrupt
feeding to a far less extent than lesions in the VMH (81). As in other
hypothalamic sites, microinjection of various orexigenic signals in the
DMH elicited feeding (13, 70, 71, 72, 73, 74, 75, 76, 77). A crucial role of neurons in the DMN
was indicated by the observation that inhibition of NPY-induced feeding
by leptin enhanced neuronal c-FOS in the DMN, the protein product of
the immediate early gene and a marker of neuronal activation (88, 89, 90).
These findings were interpreted by us to infer that the site of NPY and
leptin interaction may reside in the DMN and may represent a component
of the circuitry involved in either attenuation or inhibition of
feeding by leptin (89, 90).
DMN efferents have been traced to the VMN, and the two subdivisions of the PVN, the pPVN and magnocellular PVN (mPVN), with densest projections seen in the pPVN (81, 83, 84, 91, 92). Because there are prominent ARC efferents containing NPY to the DMN (93), it is highly likely that NPY released in this nucleus participates in stimulation of feeding. However, NPY levels in the DMN, unlike that seen in the PVN and ARC, were not elevated in response to fasting (94). Another relevant finding is that although only a few neurons in the DMN normally express NPY (95, 96), NPY gene expression was increased severalfold in the DMN in association with hyperphagia induced by disruption of neural signaling in the VMN (68) and in a genetic model of obesity and in response to lactation-induced hyperphagia (Refs. 97, 98 ; see Section III.A.4). It is not clear whether augmented NPY gene expression is associated with increased NPY availability in DMN efferents to the PVN and surrounding sites in these models of hyperphagia.
D. Paraventricular nucleus and perifornical hypothalamus
The PVN ranks second only to the VMH in terms of investigative
interest in the hypothalamic control of appetite (Fig. 1). A dense
cluster of heterogenous neurons fan out within a well defined boundary
of the PVN on either side of the roof of the third cerebroventricle in
the hypothalamus (91, 99). Several lines of evidence suggest that
neuronal elements in the PVN participate in the control of ingestive
behavior. Microinjection into the PVN of virtually all the known
orexigenic signals, NPY, GAL, orexins, GABA, opioids, norepinephrine
(NE), and epinephrine (E), stimulated feeding (13, 70, 71, 72, 73, 74, 75, 76, 77, 100),
thereby implying the existence within the PVN and its vicinity of
receptor sites for each of these signals. Additionally, microinjection
of the anorexigenic neuropeptides such as CRH, produced locally (101, 102), and leptin (78), attenuated fasting-induced feeding. Furthermore,
activation of the early gene marker, c-FOS, was augmented in neurons in
the PVN in response to administration of orexigenic (103, 104) and
anorexigenic signal molecules (88, 89, 90, 105). Another noteworthy
observation is that among other hypothalamic sites tested, such as the
VMN, the PVN is the only hypothalamic nucleus in which release of NPY,
the most potent orexigenic signal, was augmented both in
vivo and in vitro in response to fasting and before
initiation of feeding (106, 107). These seminal findings are consistent
with the idea that the PVN is one of the crucial sites for the release
of orexigenic signals, and also possibly one of the sites of
interaction of neurotransmitters/neuromodulators that inhibit feeding
by diminishing NPY release.
Whereas evidence from various experimental paradigms reinforces the notion that the PVN is a crucial site for action of orexigenic signals, it is intriguing to find that destruction of the PVN also evoked hyperphagia and abnormal body weight gain accompanied by modifications in endocrine and autonomic profiles that were quite different from those produced by VMH lesions (108, 109, 110). It is possible that, under these conditions, neural elements surrounding the PVN compensate for the PVN loss. The PFH, the neural tissue surrounding the fornix and rostral to the LH, was reported to be relatively more effective in stimulation of feeding than the PVN after the microinjection of orexigenic signals such as NE and NPY (13, 111, 112), and orexin A microinjection into the PFH stimulated feeding (100). However, involvement of the PFH within the orexigenic circuitry is rather tenuous because of the strong possibility of diffusion of NPY and NE from the PFH to the PVN and lack of evidence correlating altered secretion patterns of orexigenic signals in the PFH in response to shifts in energy balance, as seen in the PVN (106, 107).
E. Suprachiasmatic nucleus and the timing device
The pattern of ingestive behavior is a highly regulated phenomenon
in all living organisms. The drive to eat is evoked by appetite or the
sensation of hunger which, in most vertebrates, is neurally based and
entrained to activity-arousal mechanisms in the light-dark cycle. For
example, rats consume between 85–90% of their total intake during the
lights-off period. Ingestive behavior is initiated soon after onset of
the dark phase, which apparently provides either the "trigger" or
intensifies the drive for food (1). On the other hand, in nonhuman
primates maintained in the laboratory and in humans, signaling of
appetite is linked to socially acceptable or individually based
requirements. Generally, neural, metabolic, and hormonal signals that
influence ingestive behavior are stable during the period preceding and
at the onset of the drive to eat (1, 113). The negative energy balance,
which occurs during fasting, dieting, or undernourishment, intensifies
the appetite to prevent underconsumption, but it is unlikely by itself
to be the timely "trigger" for the drive to eat.
In addition, experimental findings invoke the timing mechanism in
generation of the sensation of hunger. Discrete lesions in the
suprachiasmatic nucleus (SCN), two small round nuclei resting dorsally
on the optic chiasm on either side of the third cerebroventricle (Fig. 1), result in loss of regulated feeding (114, 115). Destruction of the
VMH or disruption of neural signaling in the VMN similarly results in
unregulated phagia (18, 19, 26). In humans, several instances of
abnormal patterns of feeding characterized by a loss of regulated
consumption of meals and appearance of the nighttime binge syndrome are
associated with hyperphagia and obesity (2, 116).
In the rat, the photoperiodic-dependent circadian pattern of feeding is
undoubtedly linked to information from the SCN to the hypothalamic ARN
in two ways (Fig. 1). It is likely that initiation of nighttime feeding
results from the increased release of orexigenic signals (see
Section III.A). This may occur either directly in the
orexigenic network or indirectly by restraining the influence of
anorexigenic messengers on the release and action of orexigenic signals
(see Section IV and Fig. 7). Conversely, reinstatement of
the anorexigenic influence in a timely manner during the lights-on
period may enforce cessation of feeding. The evidence that lesions in
the SCN resulted in uninterrupted feeding is in agreement with the
notion that the SCN exerts a restraining influence on ingestive
behavior through the release of anorexigenic signals. A circadian
pattern in hypothalamic gene expression of the orexigenic signals, NPY,
GAL, and ß-END-generating precursor (POMC; Refs. 117, 118, 119, 120, 121, 122, 123), is also
consistent with a regulated pattern of daily energy management.
Interestingly, gene expression of these peptidergic signals peaked
between 0700–1500 h during the lights-on period, followed by a trough
before and during the dark phase when rats normally eat (Fig. 2 and Refs. 120, 121, 123).
Consequently, whereas this anticipatory augmentation in gene expression
of orexigenic peptides may be needed for the supply of orexigenic
peptides during the dark phase, undoubtedly feeding is regulated
independently by circadian impulses that evoke the release of these
peptides. Thus, we propose the existence of distinct neural mechanisms,
one for synthesis and the other for release of orexigenic signals,
emanating from the SCN and possibly other neural timing devices in the
brain.
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and Refs. 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135).
F. Overview of the neuroanatomical substrate associated with
appetite control
Although it is now possible to identify the hypothalamic
site or sites involved in regulation of appetite, the precise location
of the receptive neural sites for each of the orexigenic and
anorexigenic signals has not yet been ascertained (Fig. 1). The
receptors for these signals are highly concentrated in the PVN, but
they are by no means restricted to this site. The evidence that
microinjection of orexigenic signals in a number of hypothalamic sites
affects feeding argues strongly for a receptive field that extends
beyond the PVN. The fact that lesions of the ARC, VMN, DMN, or PVN
failed to subdue the drive to eat underscores a widespread receptor
field associated with appetite regulation. This observation, coupled
with the reports 1) that neural receptive sites for the anorexigenic
signals, such as leptin, insulin, CRH, urocortin, and CART, overlap
with sites containing receptors and terminal fields of orexigenic
signals, including OR (see Sections IV and V) and 2) that
orexigenic and anorexigenic neural systems are morphologically and
functionally connected, strongly support our proposal of the existence
of an interconnected ARN in the hypothalamus. We propose further that
the ARN, spanning over several hypothalamic sites including the SCN, is
composed of diverse signals (Ref. 1 ; Figs. 1 and 7). Disruptions,
either permanent as produced by lesions or neurotoxins in any part of
the ARN, or temporary as caused by imbalances in hormonal and autonomic
afferent signals, are likely to derange the tight control in the daily
management of energy homeostasis leading to hyperphagia, abnormal body
weight gain, and obesity.
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III. Orexigenic Signals |
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TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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1. Neuroanatomical pathways.
a. Source of NPY.
Although NPY-producing neurons are
located in several sites in the brain (21, 139, 140), two
subpopulations, one representing the extrahypothalamic cluster in the
brainstem (BS) including the locus coeruleus, and the other
located in the hypothalamus along the length of the ARC and in the DMN
(1, 139), apparently participate in a disparate manner in the daily
management of food intake (1, 139, 141).
NPY-producing neurons in the BS innervate various hypothalamic sites including the ARC, VMN, DMN, PVN, and surrounding regions (21, 140, 141, 142). A distinguishing feature of this population is that three other orexigenic signals, the catecholamines, NE and E, and the peptide GAL, are coproduced with NPY (21, 22). Consequently, when coreleased, these orexigenic signals are likely to interact at hypothalamic target sites (143). Experimental evidence suggests an interplay between NPY and the adrenergic system (141, 143). Transection of BS projections to the hypothalamus showed that whereas practically all the NE and E in the hypothalamus originated in the BS, only 40–50% of the NPY in various hypothalamic sites was derived from the BS (141, 142). Elimination of these BS inputs into the hypothalamus, either surgically (141, 142) or by injection of the neurotoxin, 6-hydroxydopamine (6-OHDA; Ref. 62), resulted in hyperphagia, a progressive increase in body weight and obesity. Hyperphagia in these rats was characteristically seen during the dark phase (Ref. 62 and our unpublished results). The cellular and molecular events causing increased phagia and body weight gain in these NPY- and catecholamine-deficient rats have been elucidated recently (Ref. 62 ; see Section III.A.4). The findings are consistent with the view that NPY of extrahypothalamic source along with the coexisting orexigenic signals is engaged in genesis and consolidation of neural stimuli that initiate and regulate nocturnal feeding.
Since the early demonstration that rapid time-dependent changes in NPY levels occurred in various hypothalamic sites in rats in response to fasting and refeeding (94), much attention has been directed toward defining the role of the population of NPY-producing neurons in the hypothalamic ARC. Studies involving lesions in the ARC and retrograde tracing studies demonstrated that approximately 15–20% of ARC NPY neurons innervate the PVN and DMN (93, 144). These quantitative data, together with the reports that the BS neurons contribute 40–50% of NPY in the PVN and other hypothalamic sites (141, 142), imply that the remainder of NPY in hypothalamic sites is produced either locally in the PVN or in neurons located in the vicinity. The DMN may normally be a small source of NPY in the PVN and elsewhere in the hypothalamus (93, 142), but it may contribute heavily in response to challenges that demand increased phagia (68, 97). Similarly, little NPY mRNA is detected in the PVN of normal rats but in response to disruption of neural signaling in the VMN, there is up-regulation of NPY gene expression (68). The possibility that the VMN is also a likely source of NPY for various hypothalamic sites because lesions in the VMN reduced NPY levels in the PVN and other selected hypothalamic sites (145, 146) remains to be investigated.
b. Where does NPY act to stimulate feeding?.
Since
administration of NPY into the third cerebroventricle readily
stimulated feeding in satiated rats, it was predicted that the site(s)
of NPY action may reside in and around the paraventricular region of
the hypothalamus (Fig. 1; Refs. 136, 137). Indeed, direct
application of minute amounts of NPY into various hypothalamic and
extrahypothalamic sites stimulated feeding (13, 70), and the PFH, the
region lying caudal to the PVN, was reported to be more responsive to
NPY than other sites in the neighborhood, including rostral structures
such as the POA (70, 112). Also, demonstrations that injection of NPY
into the fourth cerebroventricle stimulated feeding raised the
possibility that the NPY-receptive field may extend outside the
hypothalamus, possibly into the BS (104). Thus, as proposed in the
preceding section, it is highly likely that the field of NPY action in
stimulation of appetite is widespread in the rat brain (Fig. 1). This
is supported by the localization of NPY Y1 (18, 19, 147, 148, 149, 150, 151, 152, 153, 154, 155) and Y5 (156, 157, 158, 159, 160, 161) receptor subtypes, putative
receptors mediating stimulation of feeding by NPY, in sites
corresponding to those where microinjection of NPY stimulated feeding
(70).
Neuroactive substances, such as NPY, when microinjected into discrete
neural sites or into the cerebroventricle, travel, through volume
transmission modality, in the extracellular fluid to remote sites (162, 163). Our findings that NPY injection into either the third or the
fourth ventricle stimulated c-FOS in similar forebrain areas (103, 104)
argues for this volume transmission modality, i.e.,
movement of signals in interstitial fluid (163), to transport NPY to
distant NPY target sites. Even the endogenously released NPY in the PVN
can travel to surrounding hypothalamic sites that contain NPY receptors
and are responsive to NPY microinjection. A comparison of the
topography of c-FOS activation by NPY in the brain revealed the PVN and
DMN as sites closely associated with NPY-induced feeding (103, 104).
Indeed, pretreatment of rats with either the NPY Y1
receptor antagonist 1229U91 (164) or leptin (Fig. 3; Ref. 90) attenuated NPY-induced
feeding and c-FOS activation in the mPVN, and leptin + NPY treatment
enhanced c-FOS in the DMN. This line of investigation revealed that NPY
targets engaged in stimulation of feeding reside within the DMN-mPVN
axis (90, 164).
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c. Is NPY a physiological appetite transducer?.
Among the
known orexigenic signals, NPY is apparently the only messenger molecule
that can be considered a physiological appetite transducer in the
brain. Critical evidence to satisfy the basic criteria in support of
this view is as follows: 1) Central administration of NPY stimulated
feeding not only in satiated rats, but it also rapidly enhanced ongoing
feeding (169). 2) As expected of a physiological signal, augmentation
in food intake was dose dependent, and the response followed a
bell-shaped curve; higher doses were less effective and produced a
different pattern of feeding reflected in altered local eating rate and
time spent eating (137). 3) Continuous central infusion of NPY
reproduced the characteristic episodic nocturnal feeding pattern (170)
and various components of feeding behavior, such as cumulative food
intake, number of feeding episodes, mean episode length, total time
spent eating, eating rate (g/min), and interepisode interval, were
affected in a dose dependent manner. These similarities between the
normally occurring nocturnal feeding behavior and that reproduced by
NPY in satiated rats reinforced the view that intermittent nocturnal
feeding in rats is chemically coded and presumably dependent upon
increased NPY release and action (171). 4) This assumption was
underscored by the finding that immunoneutralization of NPY during the
dark phase of the light-dark cycle blocked nocturnal feeding (172). 5)
Enhanced NPY release, selectively in the PVN, was temporally correlated
with food consumption in rats maintained on a scheduled feeding regimen
(106). The rate of NPY release in these rats rose just before onset of
feeding and progressively decreased as the animal consumed food.
Further, these rats continued to hypersecrete NPY if food was withheld,
clearly pointing to the participation of NPY in sustaining appetite. 6)
Fasting markedly augmented NPY release in the PVN both in
vivo and in vitro (106, 107). 7) Fasting and
food restriction augmented NPY Y1 receptor mRNA in the
hypothalamus (Ref. 173 ; Fig. 4). 8)
Hyperphagia and obesity in several genetic and experimental models were
associated with modifications in NPYergic signaling. Genetically obese
ob/ob mice, db/db mice, and fatty Zucker rats (fa/fa) exhibited
increased prepro-NPY mRNA in the ARC (174, 175, 176) and NPY levels in
various hypothalamic sites and release in the PVN. 9) Augmented
NPYergic signaling in the hypothalamus, as evidenced by increases in
ARC NPY gene expression and PVN NPY levels (177, 178, 179) and release
(179, 180, 181), preceded the onset of hyperphagia induced experimentally by
streptozotocin (STZ) treatment and upon extension of the duration of
diabetes in these rats; the augmented NPY response spread from the PVN
to practically all hypothalamic sites (177, 178, 179, 180, 181). 10) Increased energy
demands during lactation, apparently met by hyperphagia, were
accompanied by increased NPYergic signaling in the ARC-PVN axis (15, 182). 11) Selective Y1 and Y5 receptor
antagonists attenuated both nocturnal feeding and that induced by
fasting (18, 19, 150, 151, 152, 155, 158, 159). 12) Studies conducted in
mice lacking either Y1 or Y5 receptors also
affirm the involvement of NPY in food intake and obesity. In mice
deficient in expression of the Y1 receptor subtype, daily
food intake and intake in response to fasting was significantly reduced
(183). Interestingly, these mice displayed a late onset of increase in
body weight. Our observations that fasting normally increases the
availability of Y1R (173) and selective Y1
antagonists inhibit feeding (18, 19), taken together with the results
from Y1 receptor knockout mice, clearly underscore a role
of NPY in control of food intake and obesity, a conclusion in line with
earlier results (184). With respect to involvement of other NPY
receptor subtypes, it has been shown that Y5R-null mice
feed normally early on, display normal feeding response to exogenous
NPY, but show late-onset obesity due to increased body weight (185).
These observations are consistent with NPY’s participation in
stimulation of feeding and reveal that Y1 and
Y5R are involved but, as documented earlier (18, 19, 184),
signaling via Y1R may be a prominent player in mediating
feeding induced by NPY. In view of the several recent reports
(186, 187, 188), it seems that either both or another subtype closely
related to Y1 and Y5 subtypes may mediate the
appetite-stimulating effects of NPY. An exciting new insight from these
studies is that not only a partial deficiency in NPY availability
induced experimentally in rats (Refs. 18, 19, 63 ; see
Section III.A.4b) but now a complete deficiency
of either Y1 or Y5 receptor subtypes results in
hyperphagia and obesity. Since in NPY-deficient rats, contribution of
increased responsiveness to NPY due to up-regulation of Y1R
(18, 19, 63) and up-regulation of GAL and GAL responsiveness have been
demonstrated (64, 66, 67), a similar pattern of shifts in signal
transduction and orexigenic signals responsible for late-onset obesity
is highly likely in Y1 and Y5 receptor mutant
mice.
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a. Neural control of NPY secretion:
i) Circadian clock. Since eating in rats occurs
primarily during the dark phase, a temporally correlated pattern of
changes in hypothalamic NPY levels, release, and synthesis was
anticipated. Akabayashi et al. (131) reported increased
prepro-NPY mRNA in the basal hypothalamus immediately preceding onset
of the dark phase, followed by a precipitous drop during the nocturnal
period of feeding. However, NPY levels remained elevated in the large
dorsomedial hypothalamic area, a part of neural tissue containing PVN
and several other adjoining nuclei, during the dark phase. A detailed
reexamination by Xu et al. (120, 121, 123) revealed that
prepro-NPY mRNA levels increased during the lights-on phase between
0700–1100 h, and then decreased and remained in the basal range
throughout the entire dark phase (Fig. 2). Evidently, a transient
elevation in NPY gene expression occurred several hours before the
onset of nocturnal feeding (Fig. 2). These findings implied that an
independent neural component, driven by the circadian clock, regulated
this daily rhythm in gene expression (120, 121, 123). Indeed, evidence
showed that up-regulation of ARC NPY gene expression, brought about by
food restriction to 4 h during the lights-on period, was sustained
throughout the 24-h period despite daily changes in the light-dark
cycle (121, 123, 189). This abolition of the daily rhythm in the ARC
NPY gene expression suggests uncoupling from the photoperiodic signals
emanating from the SCN. The neural pathways that transmit information
generated by changes in the pattern of food availability are currently
unknown.
ii) Serotonin (5-HT). Guy et al. (190) described nonsynaptic appositions between 5-HT nerve terminals and immunoreactive NPY perikarya and dendrites in the ARC. Subsequently, Dube et al. (191) showed that fenfluramine, which increases serotoninergic signaling and reduces food intake, decreased NPY levels without acutely changing release in the PVN of food-deprived rats. A possible inhibitory influence of 5-HT on NPYergic signaling was later affirmed by a series of studies by Williams and co-workers (192, 193). Pharmacological agents that activated 5-HT output inhibited NPY levels and release in the PVN concurrently with anorexia. Conversely, 5-HT antagonists stimulated feeding in conjunction with increased NPY levels in the ARC and PVN. Although these morphological and pharmacological reports collectively imply an inhibitory role of 5-HT on NPY release, the physiological relevance of the communication between serotoninergic and NPYergic signalings in the daily patterning of food intake warrants further investigation.
3. Hormonal regulation of NPY secretion. Because of its strategic distribution, circulating signals are in direct communication with the NPY system in the hypothalamus. Steroids originating from the gonads and adrenal cortex exert a modulatory influence on NPY synthesis and release (194, 195, 196, 197, 198, 199). In addition, metabolic signals relayed by the circulating peptide hormones, insulin and leptin, and cytokines can affect the NPY system directly and also are suspected to cross the blood-brain barrier and gain access to the cerebrospinal fluid through the circumventricular organs (Refs. 16, 17, 200, 201 ; see Sections III.A and V).
a. Gonadal steroids.
It has been known for a long time that
gonadal steroids modulate food intake and body weight gain in rodents
and other mammals (15). In the female, ovariectomy generally increased
food consumption and body weight gain, and estrogen replacement
reinstated the normal pattern of daily intake (15). Gonadal steroids
promoted NPY neurosecretion in the hypothalamus (194, 195, 196, 202) as
evidenced by the findings that gonadectomy decreased prepro-NPY mRNA
levels in the ARC, and testosterone replacement reinstated gene
expression and NPY levels in selected hypothalamic sites in male rats.
In ovariectomized female rats, estrogen treatment exerted a bimodal
effect. Short-term treatment induced daily changes in NPY gene
expression in the ARC with a rise in the afternoon sustained for a few
hours, a response reminiscent of the pattern of gene expression seen on
proestrus in cycling rats (195, 203). In contrast, a prolonged
uninterrupted increase in estradiol in physiological levels decreased
NPY levels selectively in the PVN and PFH and decreased NPY release
from the PVN (204). These results were interpreted to imply that the
anorectic effects of estrogen were mediated by decreased NPY release
from the PVN (204). Since NPY-producing neurons possess estrogen
receptors (194), it is highly likely that chronic estrogen action
suppressed both NPY synthesis in the ARC and release in the PVN. Baskin
et al. (205) also reported recently that estrogen inhibited
the fasting-induced increase in hypothalamic NPY gene expression.
Evidently, an underlying role of estrogen is to inhibit food intake via
direct action on the NPY pathway in the ARC-PVN of female rats.
b. Adrenal glucocorticoids.
Unlike the
hypothalamo-pituitary-gonadal axis, the interaction of the
hypothalamic-pituitary-adrenal axis with the NPY system, particularly
in relation to nocturnal feeding in the rat, has been unclear despite
the concerted efforts of a number of investigators. Experimental
evidence invoking the existence of a feedback relationship between the
adrenal cortex and hypothalamic NPY system are the following:
NPY-producing neurons are synaptically linked with CRH neurons in the
PVN (206). Microinjection of NPY into the PVN rapidly activated
pituitary ACTH and adrenal corticosterone secretion, suggesting that
this communication is excitatory in nature (207). NPY neurons in the
ARC are rich in glucocorticoid receptors (197, 198), and treatment of
adrenalectomized rats with glucocorticoids increased NPY gene
expression in the ARC in association with increased food intake and
body weight (197, 199, 208). On the other hand, unlike the effects of
gonadectomy, it is intriguing that adrenalectomy either decreased or
elicited no effect on hypothalamic NPY levels and NPY gene expression
in the ARC (209, 210, 211). Adrenalectomy failed to affect the time of onset
and pattern of nocturnal feeding, leading one to infer that NPY-induced
nocturnal feeding is not tightly coupled to the daily rhythm in the
hypothalamo-pituitary-adrenal axis. Further, in the absence of
circulating corticosterone, rats showed only a small decrease in
cumulative food intake, and NPY-induced feeding under these conditions
was minimally attenuated (211). These unremarkable effects on food
intake were attributable to the generally depressed metabolic responses
of adrenalectomized animals. Also, contrary to previous reports
(209, 210, 211, 212), recent studies showed that the fasting-induced
up-regulation of hypothalamic NPY gene expression was not dependent
upon adrenal glucocorticoids (213). Evidently, NPY can stimulate
the hypothalamo-pituitary-adrenal axis (207), but whether
glucocorticoids play a role in governing NPY output for nocturnal
feeding is uncertain.
c. Insulin.
Although it has been suggested, but not completely
proven, for a long time that pancreatic insulin may act centrally to
regulate body weight by restraining food intake (200, 201), the
hypothalamic signaling pathway underlying the anorexigenic effects of
insulin was unknown. The reports that insulinopenia produced by STZ
increased NPY levels in various hypothalamic sites in association with
hyperphagia, and insulin replacement normalized NPY levels and blocked
hyperphagia (176, 177, 178, 179, 214, 215), provided the breakthrough in firming
the concept that peripheral signals exert an inhibitory influence on
hypothalamic orexigenic pathways. NPY gene expression and NPY levels in
the PVN increased before the onset of hyperphagia in STZ-treated rats
(181). Concurrently, NPY release increased selectively in the PVN
(180). Importantly, insulin replacement, in doses that did not affect
hyperglycemia in STZ-treated rats, markedly decreased NPY release in
the PVN (180). Thus, it is highly likely that insulin per
se exerted a regulatory influence on NPY release in the PVN.
The site of insulin action is apparently the PVN because insulin
inhibited NPY release from the PVN in vitro (216).
Whether insulin inhibits NPY release directly from NPY nerve terminals
or through interneurons has not been delineated. Further, central
infusion of insulin attenuated the fasting-induced increase in NPY gene
expression (201). Since the effects of insulin on PVN NPY release were
rapid (216), it is highly likely that attenuation of the ARC NPY gene
expression by central infusion of insulin may be secondary to
inhibition of NPY release from axon terminals in the PVN (216). A
direct inhibitory action of insulin at the NPY perikaryal level is also
doubtful because central infusion of insulin failed to activate c-FOS
in the ARC (217), and insulin receptor immunoreactivity (201) has not
yet been visualized on NPY neurons in the ARC. These findings are
noteworthy when compared with the response elicited by leptin, which
also inhibited NPY synthesis (see Section V), but
readily stimulated c-FOS expression in several hypothalamic sites (89, 90). Nevertheless, there is a general consensus that insulin deficiency
results in NPY hypersecretion which, in turn, induces hyperphagia. The
physiological relevance of this postulated restraint of NPY release by
insulin in nocturnal feeding is largely unclear. Since insulin rapidly
inhibited NPY release from the PVN nerve terminals, it is possible that
the postprandial insulin rise (216) exerts a restraint, along with
leptin (Fig. 2; Refs. 121, 123), on NPY release in the PVN to
prevent hyperphagia. This nocturnal restraint on ongoing feeding, we
believe, constitutes one of the mechanisms enforcing set point in body
weight.
d. Cytokines.
During infection, CNS injury, or other
pathological conditions, anorexia leading to a loss in body weight is
manifested (9, 10, 11). Recent evidence points to a possible relationship
between increased circulating levels of cytokines and hypothalamic
NPYergic signaling in induction of anorexia during the pathological
state. Interleukin-1 was shown to decrease food intake probably by
interfering with NPY’s ability to stimulate feeding (10). Ciliary
neurotrophic factor (CNTF), another cytokine, is a neurotrophic factor,
but systemic and central injections of CNTF produced severe anorexia
(218, 219). Xu et al. (219) reported that CNTF decreased
the availability of NPY for release by suppressing NPY gene expression
in the ARC. In addition, CNTF markedly inhibited NPY-induced feeding by
decreasing Y1 abundance (173). Seemingly, CNTF, and
possibly other anorectic cytokines, acts within the hypothalamus
through their respective receptor systems to decrease NPY availability
and also to suppress the postsynaptic signal transduction processor. A
consequence of the interaction of cytokines with the NPY system, thus,
is anorexia and loss in body weight during pathological conditions.
4. Role of NPY in the etiology of hyperphagia and obesity in rodents. There are several genetic and experimentally induced models of obesity in rodents (6, 220, 221, 222). Although a hallmark of obesity is an abnormal increase in body weight attributable to multiple metabolic disturbances, partly dependent upon an imbalance in the endocrine and autonomic systems, a primary causal factor is the unrelenting drive to eat. The unregulated feeding pattern manifests either throughout the day or selectively during the dark phase. Based on the new insight that NPY is a primary appetite transducer within the interconnected orexigenic network in the hypothalamus, the possibility that modifications in NPYergic signaling may underlie hyperphagia in various models of obesity has been explored extensively.
a. Genetic models of obesity.
Evidence accumulated to date
clearly showed that in genetically obese ob/ob and
db/db mice, hyperphagia may be attributed to unabated
NPY output in the hypothalamus (174, 175, 176, 223, 224, 225). Whereas the
increase in hypothalamic NPYergic signaling in ob/ob
mice is due to leptin deficiency (16, 17, 226, 227, 228, 229, 230), in
db/db mice a defect in leptin signal transduction due to
a point mutation in the leptin receptor is the causal factor
(231, 232, 233, 234). Similarly, in fatty Zucker rats (fa/fa),
hypothalamic NPYergic signaling is augmented as evidenced by increased
NPY levels in various hypothalamic sites, NPY gene expression in the
ARC, and NPY release in the PVN (174, 176, 177, 178). The fact that
immunoneutralization of NPY in Zucker rats suppressed feeding affirmed
an important role of NPY in this model of hyperphagia (235). Leptin
resistance is believed to underlie NPY hyperactivity in Zucker rats
(236). Also, in corpulent (cp/cp) JCR-LA obese rats,
there is evidence of overactive NPYergic signaling in the hypothalamus
(237).
b. Experimental models of obesity.
In rats, hyperphagia and
abnormal body weight gain leading to obesity can be experimentally
induced by disruption of neural pathways either by localized lesions in
the hypothalamus, transection of neural pathways in the basal
hypothalamus, or by injection of neurotoxins in hypothalamic and
extrahypothalamic sites (24, 25, 26, 27, 28, 29, 30, 238). A concerted effort in our
laboratory, as summarized below, aimed at elucidating the neurochemical
basis of experimentally induced hyperphagia and obesity, revealed
disturbances in leptin-NPY signaling (see also Section
V).
i) Hyperphagia and obesity due to disruption in VMH signaling. It has been known for more than 50 yr that lesions in the VMH are associated with hyperphagia and abnormal body weight gain in rodents and humans (24, 25, 26, 29). In rats, VMH lesions produced rapid and longlasting hyperphagia resulting in overt obesity (24, 25, 26). Contrary to expectations, prepro-NPY mRNA levels in the ARC and NPY levels and release from the PVN were markedly suppressed in these rats (1, 12, 145, 146). This diminution in hypothalamic NPYergic signaling in hyperphagic VMH-lesioned rats contrasts with the hyperactive NPY system prevailing in genetic models of obesity in rodents (174, 175, 176, 214) and in diabetic rats (177, 178, 179, 180, 181). Interestingly, despite the low levels of NPY secretion, hyperphagia was dependent upon NPY because immunoneutralization of NPY completely suppressed feeding in these rats (239).
In another model in which neural signaling within the VMN was disrupted
by microinjection of the neurotoxin colchicine, transient hyperphagia,
lasting only for 4–5 days developed rapidly with an attendant increase
in body weight (18, 19, 63, 240). As in the VMH-lesioned rats, NPYergic
signaling, as demonstrated by diminution in NPY mRNA in the ARC (18, 19, 63) and NPY release in the PVN (65), diminished immediately after
colchicine injection. In these rats, hyperphagia was found to be, in
part, due to increased sensitivity to NPY (Fig. 5) and abundance of Y1
receptors in the hypothalamus, blockade of which by Y1
receptor antagonist inhibited feeding (18, 19, 63). The role of NPY
Y5 receptors in this paradigm is not clear. In addition,
even this temporary disruption in VMN function rendered rats resistant
to the action of leptin (1, 18, 19, 63). Seemingly, either one of the
targets of leptin feedback resides in the VMN or alternatively, an
intact VMN is required for relay of leptin feedback information to
sites outside the VMN. In the other models of obesity, such as that
induced by gold thioglucose in mice or by postnatal treatment of rats
with monosodium glutamate, hypothalamic NPY gene expression and NPY
levels in the PVN were similarly suppressed, and feeding in response to
NPY was increased (241, 242).
|
Taken together, evidence from genetic and experimental models of rodent obesity showed that both over- and underexpression of NPY resulted in unregulated phagia and body weight gain (1). In the case of low NPY abundance, hyperphagia is seemingly due to multiple factors brought about by a shift in the normal pattern of NPYergic signaling in the ARN. These include 1) a rapid increase in NPY Y1 receptors in the hypothalamus leading to increased sensitivity to NPY (18, 19, 63); 2) concurrent development of leptin resistance in these rats, a hypothesis in line with the hypothesis that a normally functioning VMH is necessary for the central inhibitory effect of leptin on food intake (1, 18, 19); 3) up-regulation of NPY in novel hypothalamic sites; and 4) increase in galaninergic signaling.
ii) Hyperphagia and obesity due to interruption of NE input from
the BS. Microinjection of the neurotoxin 6-OHDA into the
ventral NE bundle at the level of trochlear or oculomotor nuclei
induced hyperphagia and obesity (238, 243). Overt hyperphagia
manifesting several days after 6-OHDA injection was long lasting and
accompanied by increased rate of body weight gain (238). Interestingly,
the disruption in NPY-leptin signaling in these rats was markedly
different from that seen in the hyperphagia and obesity syndrome
produced by either electrolytic lesions in the VMH (1, 12, 145, 146) or
colchicine injection (18, 19, 63) in the VMN. The dark-phase
hyperphagia in 6-OHDA-treated rats was accompanied by two modifications
in NPY-leptin secretion. The normal nocturnal increase in leptin
secretion after eating (Fig. 2) was abolished by interruption of
catecholaminergic afferents to the hypothalamus (62). Further, it was
shown that diminution in leptin feedback was responsible for the
increase in nocturnal NPY secretion, Y5 receptor mRNA, and
hyperphagia (62).
Thus, analysis of the etiology of hyperphagia and obesity produced experimentally revealed a number of loci in NPYergic signaling within ARN that are vulnerable to disruptive insults. A provocative new concept emerging from these efforts is that both low and high abundance of NPY result in hyperphagia and obesity (1, 18, 19, 63). The evidence clearly showed that increased receptor abundance, NPY receptor sensitivity, and up-regulation of NPY in novel hypothalamic sites, together with increased availability of other orexigenic signals, such as GAL, underlie hyperphagia. Shifts in the leptin secretion pattern and development of leptin resistance also contribute toward this altered hyperphagia, producing peptidergic signaling.
B. Galanin
Galanin (GAL), a 29-amino acid peptide, has been studied
extensively for its appetite-stimulating action in the brain.
Intraventricular or intrahypothalamic injection of GAL stimulated
feeding in satiated rats (71, 72, 73, 244, 245, 246, 247, 248), and it appears that
receptive sites of GAL may be widely distributed in the rat brain.
Microinjection of GAL in the PVN, LH, VMN, and central nucleus of the
amygdala stimulated feeding in rats. As compared with NPY,
GAL-induced feeding is less remarkable, lasting for only about 30 min
with augmented response apparent at the onset of the dark phase
(71, 72, 73, 246, 248).
Unlike the discrete distribution of NPY-producing cells (21, 140),
several subpopulations of GAL-producing neurons exist in the
hypothalamus that innervate most of the hypothalamus (45). A close
anatomical and functional relationship exists between GAL and other
orexigenic signals producing neurons in the rat brain. NPY-producing
neurons were shown to be in direct communication with GAL-producing
neurons, especially in the ARC and PVN (33). Thus, GAL may, in part,
mediate NPY-induced feeding (1). Further, GAL-immunopositive nerve
terminals establish synaptic links with POMC containing dendrites and
soma in the ARC (35), raising the possibility that GAL may stimulate
the release of ß-END, which also stimulates ingestive behavior (see
Section III.C). Pretreatment of rats with naloxone (NAL), an
opiate receptor antagonist, markedly attenuated GAL-induced feeding
(246). However, because NAL pretreatment failed to completely block the
feeding response, it is quite likely that GAL directly stimulates
feeding by activating GAL receptors in hypothalamic sites (248, 249, 250, 251).
Involvement of NE in GAL-induced feeding is suggested by the reports
that GAL stimulated NE release in the PVN, and blockade of
2-adrenergic receptors with rauwolscine attenuated the
feeding stimulated by GAL (244). Furthermore, the two orexigenic
signals are coproduced in a subpopulation of neurons in the BS that
project into various hypothalamic sites, including the PVN (22), and
stimulation of modest feeding under the influence of GAL resembles that
induced by NE (72, 73). Thus, release of NE in the PVN and neighboring
sites by GAL from nerve terminals emanating from perikarya in the BS
may mediate GAL-induced feeding (22). Undoubtedly, feeding elicited by
GAL involves an interplay among various orexigenic signals, as
documented by the existence of communication lines consisting of
NPY
GALß-END and GALNE.
Whether GAL constitutes an important orexigenic signal in the daily pattern of feeding has not been clearly established. GAL-producing cells are localized in discrete subpopulations in the ARC, DMN, and PVN, but their participation in normal feeding behavior in the rat is not known. Similarly, high-affinity GAL receptors are distributed in multiple sites including those where GAL microinjection stimulated feeding (252, 253). However, GAL receptor antagonists, including M-40 that readily inhibited GAL-induced feeding, failed to suppress normal feeding in several behavioral paradigms (46, 248, 249). Infusion of GAL antisense oligonucleotides in the PVN inhibited feeding (254) but, unlike NPY, continuous GAL infusion was ineffective in increasing food intake and body weight gain (255).
Attempts to establish a correlation between the daily feeding pattern
and changes in GAL synthesis and release in the hypothalamus have not
been instructive. Increased appetite, evoked by either restricted
feeding or fasting, decreased GAL gene expression in the ARC
(256, 257, 258, 259). A small increase in GAL levels in the lateral portions of
the pPVN was observed 3 h into the dark phase (118); the
physiological significance of this in normal nocturnal feeding
is unknown. Interestingly, the daily increases in GAL gene expression
in the hypothalamus temporally coincide with those in hypothalamic POMC
mRNA but lag slightly behind those in NPY (Fig. 2; Refs. 120, 121, 123). Also, unlike NPY (174, 175, 176), GAL levels in the PVN and other
hypothalamic sites do not correlate with hyperphagia in Zucker fatty
rats (257). Consequently, additional studies are warranted to define
the precise physiological role of GAL in the daily pattern of feeding
behavior.
C. Endogenous opioid peptides
Although it has been known for a long time that opiates promote
phagia (260, 261), interest in the roles of endogenous opioid peptides
(EOP) gained momentum after the isolation and characterization of the
three biologically active opioids—ß-END, dynorphin A (DYN), and
enkephalins—in the hypothalamus (51, 52, 53). The single-copy POMC gene
encodes the POMC precursor PP, which yields the opioid, ß-END, and
the nonopioid peptides, ACTH and MSH (51, 52, 53). Within the
hypothalamus, POMC neurons, localized exclusively in the ARC, innervate
the VMN, PVN, DMN, and other areas of the hypothalamus (43, 44), where
microinjection of ß-END and opiate agonists that bind to the
µ-receptor subtype stimulate feeding (13, 23, 74). Neurons producing
the two pentapeptides, methionine-enkephalin (met-ENK) and
leucine-enkephalin (leu-ENK), are more widely distributed in the
hypothalamus, and discrete populations of leu-ENK- or
met-ENK-immunopositive perikarya have been visualized in
feeding-relevant sites, such as the ARC, VMN, DMN, and PVN, sites that
are also richly innervated by ENK-immunopositive fibers (13, 42, 44).
Although ENK were ineffective on their own, the long-acting analogs
stimulated feeding, possibly involving the 
-receptor subtype (13, 261). Central injection of the third hypothalamic opioid, dynorphin A
1–17, derived from the precursor prodynorphin, stimulated feeding by
activating the 
-opiate receptor subtype. DYN-producing cells are
also found in various regions of the hypothalamus, including the ARC
and PVN (13, 44, 261, 262).
A critical evaluation of food intake induced by various EOP showed that
opioid-evoked feeding, unlike that evoked by NPY, is generally short
lived and relatively modest (261). Extensive evidence from clinical and
animal experiments suggested that opiate receptor antagonists,
especially the µ- and -antagonists, decreased food intake (13, 262, 263, 264, 265, 266). However, whereas fasting and diabetes increased NPY mRNA,
POMC mRNA was decreased, but DYN mRNA was augmented in the PVN (258, 267). The daily rhythm in POMC gene expression was similar to that of
GAL but lagged behind the rhythm in NPY gene expression by a few hours
(Fig. 2; Refs. 120, 121, 123).
Although a large body of evidence concurs with the orexigenic nature of EOP, especially ß-END, whether these peptides subserve a relevant physiological role or represent redundant pathways in the daily management of ingestive behavior remains to be experimentally documented. However, the recent anatomical studies establishing morphological links among ß-END, GAL, and NPY and between GABA and ß-END immunoreactive pathways in the hypothalamus are highly suggestive of a role of ß-END within the orexigenic network (1, 33, 34, 35, 36, 37). Horvath et al. (34) showed that NPY immunopositive terminals established synaptic contacts with ß-END-containing dendrites and soma, suggesting that NPY may induce feeding directly on its own and also by stimulating ß-END in relevant sites such as the PVN. Indeed, NPY was shown to stimulate ß-END release in the hypothalamus (56), and NAL pretreatment attenuated feeding in response to NPY (13, 261). On the other hand, NPY decreased POMC mRNA levels in the ARC (268) and the opiate receptor antagonist, NAL, increased prepro-NPY mRNA in the ARC and increased NPY levels in the DMH (265). Morphological links between ß-END and GAL systems in the ARC and between GABA and ß-END in the ARC and PVN are suggestive of a role in regulation of GAL and GABA in the release of ß-END (33, 34, 35, 36, 37). Pharmacological evidence shows that opiate receptor antagonists decreased feeding stimulated by GAL (246) and by the GABAA receptor agonist, muscimol (13, 269). Collectively, these observations suggest that ß-END pathways may represent an important signaling modality in the operation of the interconnected orexigenic network (1).
D. Melanin-concentrating hormone
A population of neurons in the zona incerta and LH produce the
19-amino acid peptide, melanin-concentrating hormone (MCH), and project
into several hypothalamic and limbic areas (270, 271, 272, 273). Qu et
al. (274) reported potentiation of ongoing nocturnal feeding for
4–6 h by MCH administration at the onset of the dark phase. Further
studies revealed several parallels between MCH and NPY systems in the
hypothalamus. MCH augmented ongoing feeding (274), fasting stimulated
MCH gene expression in the hypothalamus, and MCH mRNA was elevated in
genetically obese ob/ob mice (274). MCH also stimulated the
hypothalamo-pituitary-adrenal axis (275). These similarities raised the
intriguing possibility that MCH may be an additional orexigenic signal
that either independently or together with NPY participates in the
hypothalamic regulation of energy homeostasis. However, this assumption
must await further experimental validation because Presse et
al. (276) reported potent anorectic effects on nighttime food
intake and suppression of body weight by extremely low doses of MCH.
Similarly, microinjection of MCH into the zona incerta-LH region
reduced feeding (276, 277). In contrast, Rossi et al. (278)
confirmed the orexigenic effects of MCH in rats, but relative to NPY,
MCH-induced feeding was small and of short duration. Further, despite
the acute stimulatory effects of MCH, cumulative 24-h intake was
unaffected, and repeated daily injections stimulated food intake for a
few days without changing the body weight. Interestingly, small lesions
in the VMN that stimulated MCH gene expression in the hypothalamus
failed to evoke hyperphagia (279, 280). Because MCH stimulated feeding
in normal satiated rats, a modulatory role of MCH in situations of
augmented appetite, as that during fasting or in genetically obese
ob/ob mice, may be envisioned.
E. Amino acids: glutamate and -aminobutyric acid
The EAA glutamate and the inhibitory amino acid -aminobutyric
acid (GABA) are produced in various hypothalamic sites and are the most
abundant neurotransmitters in the hypothalamus (47, 48, 49, 50). Intriguingly,
both neurotransmitters stimulated feeding in the rat.
N-methyl-D-aspartic acid (NMDA), the glutamate
receptor agonist, stimulated immediate and transient feeding lasting
for about 10 min only when microinjected into the LH (281, 282). It is
possible that EAA receptors involved in excitation of feeding are
located selectively in the LH and are in a position to impact the
orexigenic peptidergic network in the hypothalamus. Thus, excitation
with NMDA of neural pathways originating and/or traversing the LH may
stimulate the release of orexigenic signals such as NPY, GAL, opioids,
and orexins; however, since NMDA-induced feeding was short lived
as compared with that induced by peptides, the possibility that
neuropeptides mediate the NMDA-induced feeding is highly unlikely.
Therefore, the physiological relevance of the orexigenic action of EAA
in the integration of ingestive behavior remains to be sorted out.
In contrast, microinjection of muscimol, the GABAA receptor agonist, into several hypothalamic sites, e.g., VMN, DMN and PVN, readily stimulated feeding lasting for 30 min (74, 75, 76, 77, 269). Since these hypothalamic sites also respond to other orexigenic peptidergic signals, such as NPY, GAL, ß-END, and dynorphin, it is likely that GABAA receptors and receptors for these orexigenic peptides may be localized on the same target cells.
Recent investigations of the morphological and functional relationship
of GABA with other orexigenic signals shed light on the involvement of
the hypothalamic GABAergic network in stimulation of appetite in the
rat. Horvath et al. (283) showed that GABAergic fibers form
synaptic contacts with those ß-END-containing neurons in the ARC that
project into the diverse sites, raising the likelihood that GABAergic
synapses regulate the output of POMC-derived peptides. Additionally,
observations that the ß-subunit of GABAA receptors was
localized within the POMC-immunopositive neurons (284), and muscimol
and GABA inhibited MSH release and POMC gene expression (285), are
suggestive of an interplay of GABA with other orexigenic and
anorexigenic signals.
Recent observations that ascribe a novel physiological role to GABA are
coexpression of GABA in NPY- and GAL-producing subpopulations of
neurons in the ARC (36). Further, a large number of NPY and GABA
coexpressing neurons project into the PVN (37, 38). Because injections
of NPY and muscimol either intraventricularly or directly into the PVN
elicited a synergistic feeding response (37, 38), it is likely that
corelease of NPY and GABA in the PVN and neighboring sites may amplify
feeding. These revelations, coupled with the additional possibility
that NPY- and GABA-coexpressing cells in the ARC regulate MSH (285)
and ß-END (56) release from POMC neurons and other anorexigenic
signals, clearly favor the operation of an interconnected orexigenic
network in which peptides and GABA are intimately involved in
stimulation of appetite.
On the other hand, the excitatory effects of GABA on feeding run
counter to the prevailing notion that GABA mediates inhibitory synaptic
transmission in the brain (47). Therefore, one cannot exclude the
alternate possibility that GABA may inhibit a tonic restraint to evoke
feeding either on its own or in conjunction with NPY and other
orexigenic signals (36, 37, 38). We suggest that GABA may curtail a tonic
restraint both by decreasing MSH release and altering the response
at target sites, rendering them highly responsive to NPY. This
two-prong action of coreleased NPY and GABA thus serves to amplify
feeding (Fig. 7 and Section IV). It is also important to
note that biphasic responses to GABA, an initial inhibition followed by
excitation, are observed either when large amounts of GABA are employed
or when inhibitory synapses are activated at high frequency, causing
depolarization of postsynaptic contacts to trigger an action potential
(286, 287). Further studies devoted to understanding the precise
mechanism of GABA involvement are needed to clarify its role in the
daily patterning of feeding behavior and in the peptidergic orexigenic
network.
F. Hypocretins/orexins
Recently, a new class of orexigenic peptides was isolated and
characterized in two separate laboratories. De Lecea et al.
(288) reported that neurons producing a pair of peptides in the
hypothalamus, called hypocretins I and II (Hcrt1 and Hcrt2), were
localized in clusters in the dorsal and lateral hypothalamic area and
PFH. Immunoreactive axons emanating from these cells innervated various
forebrain structures anteriorly, such as the ARC, paraventricular
nucleus of the thalamus, POA and the septal nuclei, and caudally the
locus coeruleus and a few other sites in the BS. Almost simultaneously,
Sakurai et al. (289) reported the identification of two
neuropeptides, orexin A and orexin B, with amino acid sequences
identical to Hcrt1 and Hcrt2. Orexin-producing neurons were visualized
in similar sites in the hypothalamus. Intracerebroventricular
injections of orexin A and orexin B stimulated feeding in a
dose-related fashion with orexin A significantly more effective than
orexin B, possibly due to activation of both orexin A and orexin B
receptor subtypes (289). Orexin was found to be far less effective than
NPY in stimulating food intake and, as with NPY and MCH (Refs. 1, 19, 274 and our unpublished data), fasting up-regulated orexin
gene expression in the hypothalamus (289). A comparative evaluation of
the potency of orexins with other orexigenic signals so far examined
indicates that high doses of intracerebroventricular injections of
orexins than of other signals (GAL, MCH, or GABA) were needed to elicit
significant stimulation of feeding (our unpublished results).
Interestingly, microinjection of only orexin A in the LH, PVN, and PFH,
but not in the VMN and POA, stimulated feeding (100). Thus, although
orexin fibers terminate in large numbers of hypothalamic sites, the
orexin receptors mediating orexigenic effects may have a limited
distribution. Based on the distribution pattern of orexin receptors
(290), we suggest that orexin-2R in and around LH-PVN-PFH axis may
participate in stimulation of food intake (100). Horvath et
al. (291, 292) visualized hypocretin/orexin immunoreactive fibers
making direct contacts with NPY and leptin coexpressing neurons in the
ARC. Further, the hypocretin neurons projecting to the ARC also
appeared to be the leptin target. Consequently, it would seem that at
least a part of excitatory effects of hypocretins may result from
stimulation of NPY release in the PVN and surrounding neuronal sites.
As seen with GAL- and POMC-producing neurons, NPY-expressing cells also
established synaptic contacts with hypocretin neurons in the LH,
thereby raising the likelihood of a regulatory NPY input on
orexin-producing cells. These findings present additional supportive
evidence to strengthen the view, as expounded in this article, that
overlapping interactive appetite-stimulating pathways innervate various
hypothalamic sites in the hypothalamus to participate in coordination
of the daily pattern of feeding, and NPY system is intimately
involved in this process (Ref. 1 and Figs. 1 and 7).
G. Morphological and functional links among orexigenic signals
The extensive anatomical and experimental evidence detailed above
clearly implies and extends our hypothesis that orexigenic
signals do not act one at a time, but rather an interconnected
orexigenic network integrates the hypothalamic regulation of daily food
intake. The connectivities of NPY neurons with other orexigenic
signals, coupled with the coexpression and corelease of these signals,
exemplify the operational complexities of the orexigenic network in the
hypothalamus. Morphological evidence of a NPYß-END line of
communication, along with the observations that NPY stimulated ß-END
release and opiate receptor antagonists attenuated NPY-induced feeding,
demonstrated that NPY induces feeding on its own as well as through the
release of ß-END.
An analogous, but more extensive, communication between NPY and GAL in
several hypothalamic sites, including the ARC and PVN, exists in the
hypothalamus. Intriguingly, GAL-immunoreactive fibers also synapse with
a subset of ß-END-immunoreactive cells, and dendrites in the ARC and
the opiate receptor antagonist, NAL, inhibited feeding stimulated by
GAL, thereby revealing a functional link between GAL and ß-END in the
daily patterning of food intake. Seemingly, an interconnected
peptidergic orexigenic network of NPYGALß-END represents the
hard wiring of the hypothalamic circuitry regulating nocturnal feeding
in the rat. Furthermore, the catecholamine NE and the amino acid GABA,
coproduced with NPY and GAL, represent another mode of participation of
orexigenic signals involving postsynaptic synergistic interaction. It
is apparent that these interacting appetite-stimulating pathways may be
employed to different degrees under various physiological circumstances
and environmental challenges. That this biological redundancy is vital
for energy homeostasis is evident from NPY-knockout mice. These mutant
mice show a normal ingestive behavior; however, deletion of NPY in the
ob/ob hyperphagic obese mice produced body weight closer by
40% to wild type (293, 294). This interesting observation not only
underscores the importance of the role of NPY, but also raises the
possibility that other interacting orexigenic signals, as demonstrated
by VMN-COL model (18, 19, 63, 68), may begin to play a greater role in
the daily management of energy homeostasis when NPY signaling is
impaired.
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IV. Anorexigenic Signals |
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TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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Microinjection studies revealed that the sites of anorectic action of
CRH lies within the PVN, possibly mediated by CRH R1 or CRH R2 receptor
types (102, 300, 306). The ability of a CRH antagonist, -helical CRH
(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41) to attenuate the anorexic effects of CRH injection in the PVN
and not in the VMH suggested a site-specific involvement of PVN CRH
receptors. The report that intraventricular injection or microinjection
of CRH into the PVN, and not elsewhere in the hypothalamus, inhibited
NPY-induced feeding (306) further strengthened the notion that CRH, if
released locally in the PVN, may tonically restrain the action of
endogenous orexigenic signals.
On the other hand, several lines of evidence question the role of CRH as a physiologically relevant endogenous anorexigenic signal. There is little evidence to show that the daily pattern of CRH released locally in the PVN correlates inversely with the daily feeding pattern (211, 307). In fact, increases in CRH mRNA in the PVN, reflecting impending increased synthesis and release locally, occurred before the daily afternoon activation of the pituitary-adrenal axis, which is thought to facilitate feeding (211, 307). Further, activation of the hypothalamo-pituitary-adrenal axis is invariably observed in experimental conditions, such as fasting and food restriction, that enhance appetite and demand suppression of endogenous anorexic signals (308, 309). Adrenalectomy is known to up-regulate CRH production and release, and yet in these animals daily food intake was practically unchanged (308, 310, 311, 312). A small reduction in nocturnal feeding was attributable to glucocorticoid deficiency and the adverse impact on sympathetic nervous system activity including thermogenesis and gastrointestinal function, factors important for energy homeostasis (308, 309, 310).
Urocortin, a recently described member of the CRH family with 45%
sequence homology with CRH, has been shown to be more potent than CRH
in suppressing both the fasting-induced and nocturnal feeding (313, 314). Reduction of nocturnal feeding by urocortin was found to be due
to a reduction in meal size and not frequency of meal bouts (314). This
observation questions the physiological significance of this anorexic
peptide in the nocturnal feeding marked by robust increase in both meal
size and frequency. The topographies of urocortin and CRH-expressing
cells in the rat brain are quite different and interesting.
Urocortin-expressing cells are found in the Edinger-Westphal nucleus,
the lateral superior olive, the LH and supraoptic nucleus (SON)
(313, 314), but not in the PVN. The higher anorectic potency of
urocortin has been attributed to a relatively higher affinity of
urocortin for CRH R2 and its splice variant CRH R2. Although
urocortin-immunoreactive nerve fibers innervate lateral septum, VMH,
and medial amygdaloid nucleus, urocortin microinjections in the VMN and
not in the PVN inhibited feeding (80). Recently, Heinrichs
et al. (315) reported that increased availability of
CRH/urocortin in the hypothalamus by the chronic central infusion of
rat/human CRH(6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33), a high-affinity CRH binding protein
inhibitor, significantly decreased body weight in Zucker obese rats
that normally have reduced CRH stores in the hypothalamus.
Interestingly, since hyperphagia was unabated in these animals, these
investigators suggested that the loss in body weight was due to
CRH/urocortin-induced increase in energy expenditure and sympathetic
tone produced by thermogenesis and lipolysis, a hypothesis advocated
earlier by Rohner-Jeanrenaud and associates (309, 310). Thus, evidence
available to date is not consistent with the notion of a direct
physiological role of CRH/urocortin in the daily management of
appetite.
B. Neurotensin
Neurotensin (NT), isolated and characterized in the early 1970s
(316, 317), inhibits spontaneous and NE-induced feeding in rats, and
there is evidence that NT and dopamine act synergistically to inhibit
feeding (318). The neuroanatomical mapping of NT pathways in the rat
hypothalamus is consistent with the existence of anorexigenic pathways.
Within the hypothalamus, NT-like immunopositive neurons exist in
several distinct nuclei (319, 320, 321). Notable among these are the subset
of NT-producing neurons in the ARC, PVN, and DMN. In addition, these
and neighboring sites are richly innervated by NT-immunopositive
fibers. Interestingly, recent studies showed that a subset of
NT-positive neurons in the DMN project into both the pPVN and mPVN (83, 135), sites where microinjection of NT inhibited spontaneous feeding
(322, 323). In addition, consistent with a reciprocal interaction
between NPY and NT underlying hyperphagia in rodents, Wilding et
al. (324) reported that ob/ob mice exhibited decreased
hypothalamic NT mRNA and peptide levels in association with enhanced
NPY levels and gene expression. Similarly, NT concentrations were
reduced in several hypothalamic nuclei of Zucker obese
(fa/fa) rats (325), possibly due to impaired processing of
brain proneurotensin (326). These observations strongly favor a role of
NT in the anorexigenic circuitry; however, experimental evidence for
the physiological relevance of NT in regulation of daily pattern of
feeding is lacking.
C. Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) amide is processed from
proglucagon in intestinal L cells, and it is considered as a hormone
related to the glucagon/secretin family of peptides (327, 328). Like
several other gastrointestinal peptides, GLP-1 has been found in
various forebrain sites and in hypothalamic sites (329, 330) that
correspond with GLP-1-binding sites in the ARC and PVN (331, 332).
Extensive hypothalamic innervation by GLP-1-immunoreactive fibers
emanates apparently from a single population of
non-catecholamine-producing neurons in the caudal portion of the
nucleus of the Solitary tract (332, 333). Intraventricular
administration of GLP-1 inhibited food intake in fasted rats, a
response blocked by the concurrent administration of
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), a GLP-1-receptor antagonist (334, 335, 336). A
physiological role of GLP-1 as an anorectic or satiety factor was
suggested by the observations that exendin stimulated feeding in
satiated rats during the lights-on period, and daily injections of
exendin augmented food intake and body weight (335). Evidence suggests
that one of the sites of GLP-1 action may be the PVN where
GLP-1-immunoreactive fibers terminate and where exendin blocked
GLP-1-induced activation of c-FOS (335). The anorectic effects of GLP-1
may be mediated through NPY signaling because GLP-1 inhibited and
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) augmented NPY-induced feeding, respectively
(335, 337). Suppression of feeding by GLP-1 likely involves inhibition
of postsynaptic signaling initiated by NPY in the PVN and not by
suppression of NPY synthesis in the ARC. That GLP-1 may be an
endogenous anorectic signal was also indicated by the report that
attenuation of feeding by GLP-1 was not due to conditioned taste
aversion (338, 339). Recently Goldstone et al. (340)
reported coexpression of leptin receptor and GLP-1 mRNA in BS neurons,
and the GLP-1 receptor antagonist, exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), blocked
the leptin-induced inhibition of food intake and body weight, thereby
suggesting that the GLP-1 pathway may be one of the mediators of the
anorectic effects of leptin. In this context, it is important to note
that GLP1-R knockout mice did not exhibit any abnormalities in feeding
behavior (341).
D. Melanocortin and agouti protein
Another fascinating molecular underpinning of the hypothalamic
appetite-regulatory system is exemplified by the obesity syndrome in
agouti lethal (AY/a) mice (342, 343). In this mutant mouse,
disruption in intrahypothalamic anorexigenic signaling is caused by the
agouti protein acting through MC4 receptors. This causes maturity-onset
obesity, hyperinsulinemia, hyperglycemia, and significant increase in
linear growth accompanying fat cell hypertrophy, a phenotype akin to
most human forms of obesity (342, 343, 344, 345, 346). The melanocortin, MSH, a
nonopioid peptide encoded by the POMC gene, is distributed throughout
the hypothalamus (347, 348) and, unlike ß-END and other opiates that
stimulated ingestive behavior through activation of µ and
receptors, MSH inhibited food intake. Although not yet certain, it
remains possible that MSH-induced inhibition of feeding is mediated
through MC4-R. Of the five melanocortin receptors cloned, only two
related receptor subtypes, MC3-R and MC4-R, are primarily expressed in
the brain (349, 350, 351, 352, 353, 354). MC4-R mRNA-expressing neurons are found in more
than 100 sites in the brain including several within the hypothalamus,
such as the PVN, VMH, DMN, and nuclei that occupy the medial zone of
the hypothalamus (355, 356).
Huszar et al. (346) reported that a targeted mutation
of the MC4-R caused maturity-onset obesity, with symptoms of
hyperphagia, hyperinsulinemia, and hyperglycemia, remarkably similar to
those associated with the agouti obesity syndrome (342, 344, 346).
Neural synapses relaying information through the MSH-MC4-R pathway
seem to be intimately involved in regulating energy balance.
Involvement of hypothalamic MC4-R in feeding is supported by the
observations that intracerebral administration of a potent MC4-R
agonist inhibited feeding in hyperphagic or NPY-injected mice and in
mice with a dominant mutation at the agouti locus (AY), and
administration of a specific melanocortin antagonist (SHU9119)
counteracted the inhibitory effects of MC4-R agonists (346). It should
be noted that injections of SHU9119 potentiated nocturnal intake but
were completely ineffective in eliciting feeding in satiated rats
during the daytime. In a series of recent investigations with rather
more selective MC4-R antagonists (e.g., HS104 and HS024),
Schiöth and co-workers (357, 358, 359, 360, 361) demonstrated that these
antagonists augmented feeding in satiated rats during the daytime, and
long-term intraventricular infusion increased food intake and body
weight gain leading to obesity. Taken together, these findings suggest
a tonic restraint on feeding by melanocortin, possibly dependent on
MSH and mediated by MC4-R. Removal of this restraint, as seen in
lethal yellow (Ay/a) mice by the agouti protein, in MC4-R
knockout, or after MC4-R antagonists, leads to hyperphagia and obesity.
Although Kesterson et al. (97) failed to observe it
in several obesity models, including lethal yellow (AY/a),
MC4-R knockout, and ob/ob mice, POMC mRNA expression has
been shown to be reduced either in the rostral part or throughout the
ARC of ob/ob and db/db obese mice (362, 363, 364).
Leptin treatment of leptin-deficient ob/ob, and not
leptin-resistant db/db mice, normalized POMC mRNA
expression. Similarly, fasting-induced diminution in POMC mRNA in the
ARC was prevented by leptin treatment in rats (362, 363, 364). Based on
these observations, together with the fact that POMC neurons express
leptin receptors (362), it is reasonable to formulate the hypothesis
that POMC neurons exert a tonic restraint on feeding through
MSH-MC4-R signaling in rodents and that a diminution or defect in
the leptin-POMC-MSH-MC4-R signaling axis may, in part, be
responsible for hyperphagia in genetically obese models and for the
increased drive for food in energy-restricted rodents (362, 363, 364, 365).
However, as alluded to earlier, the fact that POMC neurons also produce
orexigenic ß-END, this singular role of MSH-MC4-R signaling within
the ARN remains unproven. Further, Boston et al. (366)
recently showed that weight gain and hyperphagic effects of defective
POMC signaling and leptin deficiency may not be linked. Indeed,
double-mutant lethal yellow (AY/a) leptin-deficient
(ob/ob) mice displayed independent and additive effects on
weight gain and, furthermore, resistance to leptin in this model was
related to desensitization of leptin signaling.
More recently, a novel gene, ART, with high homology to agouti gene
encoding agouti-related protein (AgrP), has drawn considerable
attention because of its localization in several hypothalamic sites,
including in ARC where neurons coexpressing NPY and ART/AgrP have been
visualized (39, 40). Like NPY mRNA expression, ART was expressed in
markedly higher amounts in the hypothalami of obese (ob/ob)
and diabetic (db/db) mice, a response found to be
independent of adrenal glucocorticoids (54, 55). Broberger et
al. (367) reported that NPY- and AgrP-expessing cells in the ARC
project extensively to various hypothalamic and extrahypothalamic
regions in the brain, thereby suggesting a much broader area involved
in feeding stimulated by NPY. AgrP is a potent, selective antagonist of
MC3-R and MC4-R receptor subtypes, the melanocortin receptors
implicated in control of energy balance (54, 55). Since NPY-producing
neurons in the ARC project to the PVN to release NPY for stimulation of
feeding, these findings raised the possibility that NPY and AgrP are
coreleased in the PVN from the nerve terminals of ARC NPY- and ART
mRNA-coexpressing neurons. One function of AgrP released in the PVN
would be to curtail the restraints on the inhibitory effect of MSH.
On the other hand, in keeping with the notion that the drive for food
is chemically coded through the release of orexigenic signals (1), a
large body of morphological and experimental evidence points to
NPYergic signaling for curtailing the restraint by POMC
-melanocortin receptors. NPY-producing neurons are synaptically
linked with ARC POMC neurons (34) that express Y1 receptors
(166, 167), and NPY administration promoted the release of the
orexigenic ß-END (56), inhibited the release of the anorexigenic
MSH (285), and suppressed POMC gene expression in the ARC (268).
Also, MC4-R antagonist-induced feeding appeared to be mediated by NPY
Y1 receptors (361). Thus, as proposed earlier (1, 12),
increased NPYergic signaling in genetically obese rodent models, and in
response to energy deficiency in food-deprived and food-restricted rats
and normal nighttime feeding (171), is likely responsible for
curtailing the restraint by melanocortin signaling.
These observations, when taken together with the fact that NPY-producing neurons in the ARC coexpress GABA and NPY, and GABA can coact to amplify feeding (36, 37, 38), it becomes obvious that ARC contains a unique subpopulation of neurons that coproduce NPY, the most potent orexigenic signal known, an amino acid, GABA, and a neuropeptide, AgrP; both of the coexisting signals seemingly enhance, by disparate mechanisms, the effectiveness of NPY.
Thus, we propose that a three-prong interplay, initially involving
increased NPYergic signaling on it own, and then through activation of
orexigenic ß-END, MSH, and ART, results in nocturnal feeding in
rodents. Evidence of increased NPYergic signaling, not only within the
ARC but also in the DMN in genetic and experimental models of obesity,
underscores the role of NPY as a primary neural factor in evoking
hyperphagia. Indeed, suppression of NPYergic signaling by leptin,
involving either a direct action or after entering the
brain, on NPY neurons in the ARC as in leptin-deficient
ob/ob mice (224, 368, 369), or by CNTF in leptin-deficient
fasted and food-restricted rats (218, 219), leptin-deficient
ob/ob mice (370), and leptin-resistant db/db
mice, resulted in markedly suppressed appetite. Undoubtedly, the NPY
system, on its own and through multiple channels of communication with
components of the orexigenic and anorexigenic networks,
stimulates appetite. Defective POMC signaling through the MC4-R
amplifies activation of feeding by NPY and possibly other orexigenic
signals.
E. Cocaine and amphetamine-regulated transcript
Recently, a new neuropeptide, CART (cocaine and
amphetamine-regulated transcript), was localized in the rat brain and
shown to be distributed in feeding-related sites in the hypothalamus
(57, 58, 59). Intraventricular administration of CART inhibited nocturnal
as well as fasting-induced feeding in mice and rats (60). Extensive
series of investigations in two laboratories presented strong evidence
to show that CART may be a physiologically relevant anorectic signal
(60, 61). This view is supported by the following evidence: 1)
Administration of antiserum against CART, to neutralize the anorectic
impact, increased nighttime feeding. 2) CART mRNA was localized in the
ARC, PVN, SON, rostral part of the VMH, anterior paraventricular
nucleus of the hypothalamus, and several other nuclei in the
diencephalon. Fiber projections from these CART-producing cells were
located in a large number of hypothalamic nuclei. 3) Expression of CART
mRNA in response to fasting decreased in the ARC and DMH in normal
rats. 4) In the genetically obese rodents, Zucker (fa/fa)
rats and ob/ob mice, CART gene expression in the ARC and DMH
was decreased relative to wild-type controls. 5) Leptin administration
to ob/ob mice, which lack leptin, increased CART mRNA in the
ARC to the range seen in wild-type lean control mice. This response was
associated with decrease in food intake in the ob/ob mice.
6) Interestingly, CART administration markedly inhibited the
NPY-induced feeding in fasted and normal rats. Although these results
suggested an inhibitory action of CART exerted at postsynaptic levels,
immunocytochemical studies showed a close apposition of NPY-containing
terminal with the perikarya of CART peptide-immunoreactive neurons in
the pPVN, possibly representing NPYCART communication line. This
observation is highly suggestive of a regulatory role of NPY on CART
output, in a fashion similar to NPYGAL, NPYPOMC, NPYorexin
signaling. Thus, CART-containing neurons appear to represent one of the
most powerful physiological anorexic signaling pathways.
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V. Leptin |
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TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
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) and the daily management of
energy homeostasis in rodents. This issue gains considerable
significance when the circulating pattern of leptin is correlated with
the feeding behavior of rats either feeding freely or maintained on a
restricted regimen (Fig. 2; Refs. 120, 121, 123). Apparently,
leptin does not inhibit spontaneous episodic feeding, but reduces the
amount of intake in a feeding episode (373). Chronic high levels of
leptin, achieved by intravenous or intraperitoneal injections of a
recombinant adenovirus expressing the rat leptin cDNA, resulted in a
marked reduction in food intake and body weight loss in genetically
obese mice and normal rats (374, 375). Similarly, continuous
subcutaneous infusion of leptin in the physiological range decreased
body weight and food intake in lean and several genetic models of obese
mice; chronic infusion of low doses into the third cerebroventricle
replicated the anorectic and weight-reducing effects of subcutaneously
infused leptin (376).
B. Site of action
Although several lines of evidence suggest that the hypothalamus
is the primary brain site targeted by leptin (17, 228, 229, 372), the
precise site within the hypothalamus cannot be ascertained at present.
In situ hybridization studies showed that the biologically
active, long form of the leptin receptor (OB-Rb) is produced in various
extrahypothalamic and hypothalamic sites in the mouse brain. Strong
expression of OB-Rb mRNA was seen throughout the ARC, VMH, PVN, LH, and
ventral premamillary nucleus (PMV; Ref. 368). On the other
hand, Schwartz et al. (105) visualized OB-Rb in the rat
brain in limited sites with a strong signal in the ARC and weaker
expression in the VMN and DMN and, surprisingly, no expression in the
PVN. Whether these differences in expression of OB-Rb mRNA in rats and
mice represent species differences remains to be determined.
Microinjection of leptin into the ARC, VMH, and LH inhibited 24-h food intake in rats, with the ARC being the most sensitive site (78, 79). Several laboratories have attempted to identify the hypothalamic sites of leptin action by evaluating FOS-like immunoreactivity (FLI) as a marker of neuronal activation. Woods and Stock (377) observed FLI selectively in the PVN of ob/ob but not lean mice at 3 h after a systemic injection of leptin. On the other hand, Elmquist et al. (88) reported a wider distribution of FLI in various hypothalamic and extrahypothalamic sites in response to peripheral injection of leptin in rats. In particular, FLI was visualized in the dorsomedial part of the VMH, the posterior part of the DMN and PMV. Additionally, FLI was seen sparingly in the pPVN, but remarkably, not in the ARC. In contrast, central administration of leptin elicited FLI in the PVN and DMN only (378). Another regional difference in FLI expression observed by these two laboratories was in the medial pPVN where peripheral leptin injections readily evoked FLI, but central leptin injection was ineffective (88, 378). Our studies showed that central injection of leptin stimulated FLI expression in the PVN, DMN, and PMV and little expression in the ARC (89, 90). This lack of FLI in the ARC in response to leptin is intriguing and requires further investigation.
A comparative analysis of OB-Rb mRNA localization by in situ
hybridization with those of neuronal FLI activation in response to
leptin microinjection showed considerable regional overlap within the
hypothalamus, allowing one to infer that the putative sites of leptin
action correspond closely to the broad neuroanatomical substrate
concerned with the control of energy homeostasis (Fig. 1; see
Sections III and IV). The list of leptin target
neuronal systems has recently grown to include subpopulations of
orexigenic and anorexigenic signal-producing neurons, thereby raising
the possibility of a complex neuronal substrate for leptin feedback
involving diminution or restraint in the output of orexigenic signals
concurrent with activation of anorexigenic signals (see below).
1. Orexigenic signal-producing network.
a. NPY signaling:
i) Leptin and NPY synthesis and release. Perhaps the
most revealing finding of the adipocyte-hypothalamic signaling pathway
is that a subpopulation of NPY-producing cells in the hypothalamus may
be one of the targets of leptin action. The observations that 1) OB-Rb
receptor and NPY are coexpressed in the ARC (369, 379, 380, 381); 2) leptin
inhibited NPY gene expression in the ARC of genetically obese
(ob/ob) mice and in normal and food-deprived rats (224, 372); and 3) reduced NPY levels in the ARC, DMN, and PVN (372),
suggested that leptin may regulate the availability of NPY for release.
Leptin decreased NPY release in vitro from hypothalamic
fragments of ob/ob mice perifused with corticosterone,
but not in the absence of corticosterone (224), and KCl-induced NPY
outflow from the hypothalamus was attenuated by leptin (382). Although
these findings suggested that leptin may rapidly decrease NPY release
from the corticosteroid-primed whole hypothalami of leptin-deficient
mice, similar rapid action of leptin on NPY release has not been
replicated in rats. There was no effect of leptin on NPY release from
the microdissected ME-ARC, VMH, or PVN of normal or food-deprived rats
(S. P. Kalra, unpublished), and NPY efflux in perfusates collected
from PVN were not affected by leptin (383). It is possible that NPY
release may not be the primary locus of action; instead, leptin may
restrain feeding by restricting the availability of NPY on a long-term
basis and by counteracting the orexigenic effects of NPY at
postsynaptic target sites (see below).
ii) Leptin and NPY-induced feeding. Leptin suppressed
NPY-induced feeding acutely and on a long-term basis (219). Daily
injection of leptin decreased food intake and body weight gain
concomitant with not only diminished NPY gene expression in the ARC but
also by interfering with NPY action (219). In long-term leptin-treated
rats, stimulation of feeding in response to intraventricular NPY was
nearly abolished (Fig. 6). Even in the
ob/ob mice with little endogenous leptin, Smith
et al. (384) reported a dose-dependent decrease in
NPY-induced feeding by exogenous leptin. Leptin has also been reported
to suppress GAL- and MCH-induced feeding (385).
|
; Refs. 89, 90). A
similar diminution in mPVN FLI was noted when NPY-induced feeding was
inhibited by the NPY Y1 receptor antagonist, 1229U91 (164).
Evidently, a subpopulation of neurons selectively in the mPVN is the
target of NPY and leptin interaction (Fig. 3). In addition, since
leptin and NPY together increased FLI in the DMN, it is likely that
diminution in FLI expression by leptin in the mPVN may be secondary to
the synergistic activation of DMN neurons by leptin and NPY (90, 164).
Thus, the participation of the DMN-mPVN axis in the restraining effects
of leptin on NPY-induced feeding sets the stage for further
exploration of these two hypothalamic nuclei.
b. Other orexigenic signals.
Håkansson et
al. (379) recently localized the OB receptor (OB-Rb) with an
antibody that recognized all isoforms of this receptor on the periphery
of NPY- and POMC-producing neurons in the ARC and MCH-producing neurons
in the LH. Coexpression of OB-Rb with POMC mRNAs, and with GAL mRNA in
the ARC, also has been reported (362, 363). Orexin-producing neurons in
the LH also express OB-Rb (291, 292). Taken together, these findings
raise the possibility that POMC-, MCH-, GAL-, and orexin-containing
neurons may be the targets of leptin. Leptin suppressed feeding evoked
by MCH and GAL. Like NPY, whether the simultaneous diminution in the
secretion of these orexigenic peptides underlies reduction of food
intake and body weight in the daily management of energy balance
remains to be demonstrated.
2. Anorexigenic signal-producing network. Localization of OB-R
immunoreactivity or OB-Rb mRNA showed that the leptin receptor is
coexpressed in neurons producing the anorexigenic peptides,
ACTH-positive POMC neurons in the ARC (362, 363), and GLP-1-producing
neurons in the nucleus of the solitary tract (340, 386). Although
inconsistent with a recent report (387), leptin injections to
leptin-deficient ob/ob mice suppressed POMC mRNA (363). The
decrease in the ARC POMC mRNA due to fasting was also prevented by
leptin treatment. These results have been interpreted to mean that
increased POMC mRNA in leptin-treated rats represents increased release
of MSH in the PVN which, in turn, decreases feeding. However, this
is uncertain because of the possibility that increased POMC mRNA also
reflects increased release of the orexigenic opioid peptides (56). On
the other hand, the ability of leptin to inhibit food intake was
attenuated by blockade of MC4 receptors, suggesting a role of
MSH-MC4-R in mediating inhibition of food intake (365), a finding
not in line with those of Boston et al. (366).
Interestingly, the GLP-1 receptor antagonist exendin blocked leptin’s
effects and because GLP-1 producing neurons in the nucleus of the
solitary tract express OB-Rb, it is also possible that GLP-1 neurons
are a potential target for leptin (340, 386). Consequently, whether
leptin suppressed feeding primarily by diminishing the release and/or
action of orexigenic signals alone or together with augmenting the
signaling of anorexigenic peptides remains to be clarified.
C. Is leptin a physiological satiety signal?
1. Leptin synthesis and secretion in relation to feeding behavior.
a. Correlation with ingestive behavior in rodents.
As
summarized in the preceding section, overwhelming evidence demonstrates
that exogenous leptin inhibits food intake in rodents. A few exceptions
are rats with either lesions in the VMH (145, 146) or disruption of
neural signaling by neurotoxins in the VMN (18, 19, 63, 388) and the
genetically obese rats (fa/fa Zucker) and mice
(db/db and AY/a Agouti yellow; 16,
227–229). These rodents are obese, hypersecrete leptin, and are
resistant to the central antiappetite action of leptin.
The precise role of leptin in the daily patterning of ingestive
behavior is not yet clear. The assumption that leptin restrains food
intake to maintain body weight within the narrow set point for an
individual is not supported by current data on the daily patterns of
adipocyte leptin gene expression and circulating levels. Rodents are a
nocturnal species consuming almost 80–90% of their daily intake
during the lights-off period in conjunction with increased general
activity. There is little, if any, intake before the onset of the dark
phase. Arousal and increased general activity normally precedes
ingestive behavior after onset of the dark phase. During the lights-on
period, general activity is minimal with rats displaying a few
short-lived feeding episodes (389). Saladin et al. (390)
reported that leptin mRNA levels in adipose tissue of mice showed a
daily rhythm with lowest levels during the entire lights-on phase, but
it increased during the dark phase, beginning at 2000 h and
rapidly peaking at 0400 h. On the other hand, the daily pattern of
serum leptin levels was different and lagged considerably behind the
peaks and valleys in leptin mRNA levels (390). Serum leptin levels in
mice were lowest at 2 h into the dark phase (1800 h, lights on
0400–1600 h), followed by a rise beginning at 2400 h and peaking
by 0400 h. A slow rate of decrease in circulating leptin levels
occurred throughout the lights-on phase to reach nadir at 2 h into
the dark phase. In our studies (120, 121, 123), leptin mRNA in rat
adipocytes increased abruptly before the onset of feeding at the time
of lights off (1900 h; Fig. 2). Thereafter, during the intense period
of feeding, leptin mRNA levels increased to peak at 2300 h and
then declined along with the cessation of nighttime food consumption.
This daily pattern in the steady state levels of adipocyte leptin mRNA
and leptin-R is apparently characterized by enhanced gene expression
before onset of the dark phase and ingestive behavior. This observation
is strongly suggestive of the existence of an independent mechanism
regulating OB gene expression that is not driven by lights-off signal.
Surprisingly, on the other hand, a markedly different temporal pattern
in serum leptin levels also exists in these rats. Leptin secretion
increased after lights off to peak at 2300 h and then fell
progressively during the late dark-phase concomitant with ongoing
feeding. Leptin secretion thereafter decreased to a nadir at 1100
h during the light phase, when rats display little feeding behavior.
This dichotomy in the temporal patterns of leptin gene expression and circulating leptin levels in mice and rats provides new interpretations for the complex role of leptin in regulating daily ingestive behavior and maintenance of body weight within the set point of the individual. Evidently, neither the onset of feeding nor the lights-off signal is the trigger for increased gene expression in adipocytes. Instead, we propose that a distinct neural mechanism, which occurs in anticipation of the animal’s need to increase leptin secretion during the nocturnal feeding, initiates this antecedent increase in leptin gene expression. However, maintenance of nocturnal high levels of leptin gene expression and secretion are coupled to food intake because overnight fasting abolished the late dark-phase increments in leptin gene expression (213, 391), and restricting the availability of food to lights-on phase accordingly moved increased leptin secretion into the interval of robust feeding (120, 121, 123).
Since blood leptin levels are basal during the lights-on phase,
contemporaneous with little evidence of feeding, it is reasonable to
assume that the feeding-associated rise in leptin secretion constitutes
the feedback signal to the hypothalamus, to first diminish and
eventually terminate the urge to eat. This impact is sustained during
the lights-on period interspersed with very few brief feeding episodes.
Thereafter, as increased availability of Ob-Rb imparts enhanced
sensitivity to leptin, as reflected by augmented hypothalamic
Ob-Rb gene expression, the feeding-associated leptin rise may greatly
assist in reducing appetite (Fig. 2). Overexpression of hypothalamic
Ob-Rb mRNA, associated with reduced leptin levels and increased
sensitivity toward leptin action, although not consistently observed
(392, 393), is in line with the interplay between antecedent increased
leptin sensitivity and prandial rise in circulating leptin as
responsible for exerting a longlasting suppression of feeding seen
during the lights-on phase.
b. Correlation with ingestive behavior in humans.
It is well
documented that Ob mRNA levels in adipocytes and serum leptin levels
correlate with body fat mass and weight in normal and obese patients
(220, 227, 394, 395, 396, 397). Fasting rapidly decreased secretion and,
conversely, overfeeding for short or long periods augmented leptin
secretion parallel with the attendant increases in percentage of body
fat (394, 395, 396, 397, 398). In humans, there is a highly organized pattern of
leptin secretion over a 24-h period. In general, the circadian pattern
is characterized by basal levels between 0800–1200 h, rising
progressively to peak between 2400–0400 h, and receding steadily to a
nadir by 1200 h (400). Unlike that in rodents, increases in leptin
secretion do not appear to be driven by meal patterns. Leptin is
secreted in a regular pulsatile fashion with an interpeak interval of
about 44 min (400, 401), and the circadian rhythm is attributable
solely to increased pulse height. Interestingly, the circadian pattern
of leptin secretion is preserved in obese patients, and elevated blood
levels could be accounted for by increased leptin pulse height. In
women with anorexia nervosa, leptin levels are maintained in the low
range (402). These circadian and pulsatile patterns of fluctuations in
blood leptin levels imply that neural and neurohumoral components in
the brain may regulate leptin secretion from adipocytes. Because of the
rapid development of leptin resistance in humans, our new challenge is
to elucidate the mechanism by which these two patterns of leptin
secretion regulate appetite and body weight gain in humans.
D. Leptin signal transduction and leptin resistance
A limited number of studies examined the electrophysiological
events triggered by leptin in target cells in the ARC and VMH. Leptin
hyperpolarized glucose-responding hypothalamic cells by activation of
potassium currents in lean, but not Zucker (fa/fa), rats
(403). In rat brain slice preparations, leptin rapidly altered synaptic
transmission in ARC neurons by attenuating evoked excitatory action
potentials (404). Localization of Ob-Rb protein in the hypothalamus and
extrahypothalamic sites revealed another intriguing finding (405).
Light microscopic analysis showed Ob-Rb immunolabeling associated with
the Golgi apparatus of the neurons and glial cells in the ARC, VMN, and
pPVN and mPVN (405). Ob-Rb immunolabeling was selectively confined to
cis, medial, and trans cisternae and absent in
vesicles in close proximity to either faces of the stack. These novel
observations are suggestive of a role for leptin in modulating
intracellular events, possibly in processing of
neurotransmitter/neuromodulators, the functional property of the Golgi
apparatus.
Further, the insight that Ob-Rb has homology to members of class I cytokine receptor family, including those of the potent anorectic CNTF (173, 218, 219) sparked investigation to explore similarities in molecular events in intracellular signal transduction engaged by cytokines and leptin (406). The current evidence indicated that leptin elicited a dose-dependent activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) in the hypothalamus of mice and rats (407, 408, 409). This activation is suspected to augment c-fos expression, ultimately culminating in modulation of orexigenic and anorexigenic output. The identity of tyrosine kinases (Janus Kinases, JAKS) and other upstream cascades subsequent to binding of leptin to Ob-Rb remains to be ascertained (409, 410).
Leptin insensitivity in many rodent models of obesity is apparently due to structural aberrations in Ob-Rb itself or defective transport of leptin across the blood-brain barrier. There is also a strong possibility that leptin resistance may result from defects located downstream in the signal transduction pathway. Soon after the cloning of a family of cytokine-inducible inhibitors of signaling, the SOCS (suppressor-of-cytokine signaling; Ref. 411), Bjorback et al. (412) reported that leptin activated the expression of SOC-3 in the hypothalamic areas corresponding to Ob-Rb expressing cells. Further, forced expression of SOC-3 blocked leptin-induced signal transduction in a mammalian cell line and, interestingly, basal SOC-3 mRNA in the ARC and DMN were elevated in leptin resistance model, lethal yellow (Ay/a) mice. The fact that SOC-3 is a leptin-inducible negative intracellular regulator of leptin signal transduction, one can envision that up-regulation of SOCS contributes toward development of leptin resistance in several rodent models and obese individuals.
|
VI. Summary |
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|
TopAbstractI. IntroductionII. Neuroanatomical Substrate...III. Orexigenic SignalsIV. Anorexigenic SignalsV. LeptinVI. SummaryReferences |
|---|
, a distinct ARN in the
hypothalamus is involved in the control of nocturnal appetite. At least
four basic elements operate within this ARN. These are: 1) A discrete
appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and
orexin transduces and releases appetite-stimulating signals. 2)
Similarly, anorexigenic signal-producing pathways (e.g.,
CRH, GLP-1, MSH, and CART) orchestrate neural events for dissipation
of appetite and to terminate feeding, possibly by interrupting NPY
efflux and action at a postsynaptic level within the hypothalamus. It
is possible that some of these may represent the physiologically
relevant "off" switches under the influence of GABA alone, or AgrP
alone, or in combination with NPY released from the NPY-, GABA-, and
AgrP-coproducing neurons. 3) Recent evidence shows that neural elements
in the VMN-DMN complex tonically restrain the orexigenic signals during
the intermeal interval; the restraint is greatly aided by leptin’s
action via diminution of orexigenic (NPY) and augmentation of
anorexigenic (GLP-1, MSH, and CART) signals. Since interruption of
neurotransmission in the VMN resulted in hyperphagia and development of
leptin resistance, it seems likely that the VMN is an effector site for
the restraint exercised by leptin. The daily rhythms in leptin
synthesis and release are temporally dissociable because the onset of
daily rise in leptin gene expression in adipocytes precedes that in
leptin secretion. Nevertheless, these rhythms are in phase with daily
ingestive behavior because the peak in circulating leptin levels
occurs during the middle of the feeding period. These observations,
coupled with the fact that circulating levels of leptin are directly
related to adiposity, pose a new challenge for elucidating the precise
role of leptin in daily patterning of feeding in the rat. 4) A neural
timing mechanism also operates upstream from the ARN in the daily
management of energy homeostasis. Although the precise anatomical
boundaries are not clearly defined, this device is likely to be
composed of a group of neurons that integrate incoming internal and
external information for the timely onset of the drive to eat.
Evidently, this network operates independently in primates, but it is
entrained to the circadian time keeper in the SCN of rodents. Apart
from its role in the onset of drive to eat, the circadian patterns of
gene expression of NPY, GAL, and POMC denote independent control of the
timing device on the synthesis and availability for release of
orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated
constituent of the timing mechanism in this context, because lesions in
each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the primary sites of release and action of various orexigenic and anorexigenic signals. A novel finding is the identification of the interconnected wiring of the DMN-mPVN axis that may mediate leptin restraint on NPY-induced feeding. The chemical phenotypes of leptin and NPY target neurons in this axis remain to be identified.
These multiple orexigenic and anorexigenic pathways in the hypothalamic ARN appear to represent redundancy, a characteristic of regulated biological systems to provide a "fail-safe" neural mechanism to meet an organism’s constant energy needs for growth and maintenance. Within this formulation, the coexisting orexigenic signals (NPY, NE, GAL, GABA, and AgrP) represent either another level of redundancy or it is possible that these signals operate within the ARN as reinforcing agents to varying degrees under different circumstances.
A most revealing outcome to explain the pathophysiology of unregulated feeding and hyperphagia emanated from the careful analysis of the relationship between NPY synthesis and release and food intake. Both overabundance and low abundance of NPY in the ARC-PVN axis appear to lead to unregulated phagia and attendant obesity. Overabundance of NPY, as evident in genetically obese and diabetic rodents, stimulated hyperphagia by increased postsynaptic receptor stimulation. On the other hand, in conditions of marked diminution of NPY availability at target sites, as seen in rats with disrupted neural signalings in the VMH, postsynaptic receptor supersensitivity and increased abundance of NPY receptors exaggerate the drive for food. Diminution in NPY production in the ARC experimentally by disruptions in VMN signaling resulted in up-regulation of NPY in novel sites, concomitant with up-regulation of GAL and increased responsiveness to GAL. Similar responses in NPY and GAL signaling were seen in genetic models of obesity. Thus, one can envision that a loss of the tight control on NPY neurosecretion resulting either in overabundance or low abundance evoked hyperphagia and attendant increase in body weight.
Detailed examination of the disturbances in neural and molecular
sequelae in genetically obese rodents showed that impaired anorexigenic
signaling also produced unregulated feeding and abnormal body weight
gain. This is best exemplified by two rodent models, one displaying
leptin and the other MCR-4 receptor deficiency in the hypothalamus.
Deficiency in CART production in ob/ob and Zucker rats is
another example. Thus, an imbalance in the operation of either
orexigenic or anorexigenic pathways in the ARN (Fig. 7) perturbs the
regulatory microenvironment leading to hyperphagia. Among anorexigenic
signals, cytokines are the only molecules identified to date that
produce anorexia and severe loss of body weight; lack of leptin, but
not other members of the cytokine family, leads to hyperphagia.
Evidence to date from our laboratory clearly showed that impaired signaling within the VMN is responsible for imparting leptin resistance. Ongoing intensive research to identify sequalae in signal transduction downstream from Ob-Rb activation is likely to reveal new intracellular molecules engaged in sustaining leptin insensitivity.
This expanding knowledge of the hypothalamic ARN has provided new
insights, at several levels, for designing therapeutic strategies to
control appetite and body weight (Fig. 7). It is apparent that the
efficacy of antiappetite drugs will depend both on their effectiveness
to curtail the availability of orexigenic and/or enhance the
availability of anorexigenic signals at target sites while preventing
the development of receptor supersensitivity (Ref. 1 and Fig. 5).
Future research should focus on characterizing the precise
morphological links among components of the appetite-regulating
circuitry and on elucidating the cellular and molecular sequelae
associated with the orderly progression of information leading to,
during, and after synchronized feeding episodes. Such insight is likely
to shed light on various loci in the circuitry that may be disrupted by
inappropriate environmental and hormonal events underlying the
pathophysiology of hyperphagia and abnormal body weight gain.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
1 The research summarized in this article was supported by NIH Grant
DK-37273 (to S.P.K.) and NS-32727 (P.S.K.). 
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References |
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C. J. Groves, E. Zeggini, M. Walker, G. A. Hitman, J. C. Levy, S. O'Rahilly, A. T. Hattersley, M. I. McCarthy, and S. Wiltshire Significant Linkage of BMI to Chromosome 10p in the U.K. Population and Evaluation of GAD2 as a Positional Candidate Diabetes, June 1, 2006; 55(6): 1884 - 1889. [Abstract] [Full Text] [PDF]
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B. S. Muhlhausler, C. L. Adam, P. A. Findlay, J. A. Duffield, and I. C. McMillen Increased maternal nutrition alters development of the appetite-regulating network in the brain FASEB J, June 1, 2006; 20(8): 1257 - 1259. [Abstract] [Full Text] [PDF]
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L. Pinilla, R. Fernandez-Fernandez, E. Vigo, V. M. Navarro, J. Roa, J. M. Castellano, R. Pineda, M. Tena-Sempere, and E. Aguilar Stimulatory effect of PYY-(3-36) on gonadotropin secretion is potentiated in fasted rats Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1162 - E1171. [Abstract] [Full Text] [PDF]
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L. Givalois, G. Naert, L. Tapia-Arancibia, and S. Arancibia Involvement of brain-derived neurotrophic factor in the regulation of hypothalamic somatostatin in vivo. J. Endocrinol., March 1, 2006; 188(3): 425 - 433. [Abstract] [Full Text] [PDF]
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F. Kreier, Y. S. Kap, T. C. Mettenleiter, C. van Heijningen, J. van der Vliet, A. Kalsbeek, H. P. Sauerwein, E. Fliers, J. A. Romijn, and R. M. Buijs Tracing from Fat Tissue, Liver, and Pancreas: A Neuroanatomical Framework for the Role of the Brain in Type 2 Diabetes Endocrinology, March 1, 2006; 147(3): 1140 - 1147. [Abstract] [Full Text] [PDF]
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M. Kobashi, Y. Shimatani, K. Shirota, S.-Y. Xuan, Y. Mitoh, and R. Matsuo Central neuropeptide Y induces proximal stomach relaxation via Y1 receptors in the dorsal vagal complex of the rat Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2006; 290(2): R290 - R297. [Abstract] [Full Text] [PDF]
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D. Burdakov, S. M Luckman, and A. Verkhratsky Glucose-sensing neurons of the hypothalamus Phil Trans R Soc B, December 29, 2005; 360(1464): 2227 - 2235. [Abstract] [Full Text] [PDF]
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L. Ste. Marie, S. Luquet, T. B. Cole, and R. D. Palmiter Modulation of neuropeptide Y expression in adult mice does not affect feeding PNAS, December 20, 2005; 102(51): 18632 - 18637. [Abstract] [Full Text] [PDF]
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A. Tabarin, Y. Diz-Chaves, M. d. C. Carmona, B. Catargi, E. P. Zorrilla, A. J. Roberts, D. V. Coscina, S. Rousset, A. Redonnet, G. C. Parker, et al. Resistance to Diet-Induced Obesity in {micro}-Opioid Receptor-Deficient Mice: Evidence for a "Thrifty Gene" Diabetes, December 1, 2005; 54(12): 3510 - 3516. [Abstract] [Full Text] [PDF]
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S. Dagogo-Jack, G. Tykodi, and I. Umamaheswaran Inhibition of Cortisol Biosynthesis Decreases Circulating Leptin Levels in Obese Humans J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5333 - 5335. [Abstract] [Full Text] [PDF]
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G. K. Ford, K. A. Al-Barazanji, S. Wilson, D. N. C. Jones, M. S. Harbuz, and D. S. Jessop Orexin Expression and Function: Glucocorticoid Manipulation, Stress, and Feeding Studies Endocrinology, September 1, 2005; 146(9): 3724 - 3731. [Abstract] [Full Text] [PDF]
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J. R. Metz, E. J. W. Geven, E. H. van den Burg, and G. Flik ACTH, {alpha}-MSH, and control of cortisol release: cloning, sequencing, and functional expression of the melanocortin-2 and melanocortin-5 receptor in Cyprinus carpio Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R814 - R826. [Abstract] [Full Text] [PDF]
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P. J. Currie, A. Mirza, R. Fuld, D. Park, and J. R. Vasselli Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R353 - R358. [Abstract] [Full Text] [PDF]
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E. Karteris, R. J. Machado, J. Chen, S. Zervou, E. W. Hillhouse, and H. S. Randeva Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1089 - E1100. [Abstract] [Full Text] [PDF]
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J. D. Coppola, B. A. Horwitz, J. Hamilton, J. E. Blevins, and R. B. McDonald Reduced feeding response to muscimol and neuropeptide Y in senescent F344 rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1492 - R1498. [Abstract] [Full Text] [PDF]
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S. P. Kalra, N. Ueno, and P. S. Kalra Stimulation of Appetite by Ghrelin Is Regulated by Leptin Restraint: Peripheral and Central Sites of Action J. Nutr., May 1, 2005; 135(5): 1331 - 1335. [Abstract] [Full Text] [PDF]
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M. J. Bradbury, U. Campbell, D. Giracello, D. Chapman, C. King, L. Tehrani, N. D. P. Cosford, J. Anderson, M. A. Varney, and A. M. Strack Metabotropic Glutamate Receptor mGlu5 Is a Mediator of Appetite and Energy Balance in Rats and Mice J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 395 - 402. [Abstract] [Full Text] [PDF]
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R. Fernandez-Fernandez, E. Aguilar, M. Tena-Sempere, and L. Pinilla Effects of Polypeptide YY3-36 upon Luteinizing Hormone-Releasing Hormone and Gonadotropin Secretion in Prepubertal Rats: In Vivo and in Vitro Studies Endocrinology, March 1, 2005; 146(3): 1403 - 1410. [Abstract] [Full Text] [PDF]
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K. Bugarith, T. T. Dinh, A.-J. Li, R. C. Speth, and S. Ritter Basomedial Hypothalamic Injections of Neuropeptide Y Conjugated to Saporin Selectively Disrupt Hypothalamic Controls of Food Intake Endocrinology, March 1, 2005; 146(3): 1179 - 1191. [Abstract] [Full Text] [PDF]
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K. Wynne, S. Stanley, B. McGowan, and S. Bloom Appetite control J. Endocrinol., February 1, 2005; 184(2): 291 - 318. [Abstract] [Full Text] [PDF]
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V. Locatelli and A. Torsello Pyruvate and Satiety: Can We Fool the Brain? Endocrinology, January 1, 2005; 146(1): 1 - 2. [Full Text] [PDF]
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M. Bohlooly-Y, B. Olsson, C. E.G. Bruder, D. Linden, K. Sjogren, M. Bjursell, E. Egecioglu, L. Svensson, P. Brodin, J. C. Waterton, et al. Growth Hormone Overexpression in the Central Nervous System Results in Hyperphagia-Induced Obesity Associated With Insulin Resistance and Dyslipidemia Diabetes, January 1, 2005; 54(1): 51 - 62. [Abstract] [Full Text] [PDF]
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C. B. Kaelin, A. W. Xu, X.-Y. Lu, and G. S. Barsh Transcriptional Regulation of Agouti-Related Protein (Agrp) in Transgenic Mice Endocrinology, December 1, 2004; 145(12): 5798 - 5806. [Abstract] [Full Text] [PDF]
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M. Felies, S. von Horsten, R. Pabst, and H. Nave Neuropeptide Y stabilizes body temperature and prevents hypotension in endotoxaemic rats J. Physiol., November 15, 2004; 561(1): 245 - 252. [Abstract] [Full Text] [PDF]
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G Tulipano, A V Vergoni, D Soldi, E E Muller, and D Cocchi Characterization of the resistance to the anorectic and endocrine effects of leptin in obesity-prone and obesity-resistant rats fed a high-fat diet J. Endocrinol., November 1, 2004; 183(2): 289 - 298. [Abstract] [Full Text] [PDF]
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J. Chen and H. S. Randeva Genomic Organization of Mouse Orexin Receptors: Characterization of Two Novel Tissue-Specific Splice Variants Mol. Endocrinol., November 1, 2004; 18(11): 2790 - 2804. [Abstract] [Full Text] [PDF]
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X. Fioramonti, A. Lorsignol, A. Taupignon, and L. Penicaud A New ATP-Sensitive K+ Channel-Independent Mechanism Is Involved in Glucose-Excited Neurons of Mouse Arcuate Nucleus Diabetes, November 1, 2004; 53(11): 2767 - 2775. [Abstract] [Full Text] [PDF]
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