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Emerging Therapeutic Strategies for Obesity

Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Veterans Administration Puget Sound Health Care System, Seattle, Washington 98108

Correspondence: Address all correspondence and requests for reprints to: David E. Cummings, M.D., Associate Professor of Medicine, University of Washington, Veterans Administration Puget Sound Health Care System, 1660 South Columbian Way, S-111-Endo, Seattle, Washington 98108. E-mail: davidec{at}u.washington.edu

	Abstract

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss.

I. The Obesity Crisis

II. Neuroendocrine Regulation of Body Weight

III. Principles for the Design of Antiobesity Therapeutics

IV. Stimulators of Catabolic Pathways

A. Leptin and leptin-receptor agonists

B. Strategies to overcome obesity-related leptin resistance

C. Second- and higher-order targets of leptin action: melanocortins

D. Ciliary neurotrophic factor

E. Subtype-selective serotonin-receptor agonists

V. Inhibitors of Anabolic Neuropeptides

A. Neuropeptide Y and its many receptors

B. Melanin-concentrating hormone

VI. Gastrointestinal Peptides That Regulate Food Intake

A. Glucagon-like peptide-1

B. Peptide-YY_3-36

C. Oxyntomodulin

D. Amylin

E. Ghrelin

VII. Bringing It All Together: Cannabinoid-1 Receptor Antagonism

VIII. Closing Comments

	I. The Obesity Crisis

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
THE PANDEMIC OF obesity and its complications continues inexorably to worsen (1), yet our pharmaceutical armamentarium to combat this disease remains surprisingly limited and impotent in the face of the challenge. The National Institutes of Health recommend pharmacotherapy, in conjunction with lifestyle modification, for all obese individuals (i.e., body mass index 30 kg/m²) and for overweight persons with a body mass index greater than 27 kg/m² accompanied by at least one comorbidity (2). Given the startling prevalence of overweight and obesity, this policy mandates pharmacotherapy for approximately half of all American adults. Yet only three medications—sibutramine, phentermine, and orlistat—are approved in the United States to treat obesity, and each of these typically promotes no more than 5–10% loss of body weight (3). Although such modest weight loss confers disproportionate health benefits, it is far from a cure for the problem. Thus, developing a thorough understanding of the neuroendocrine regulation of body weight is a pressing need to help design medicines that can safely promote more substantial weight loss. Herein we highlight selected advances and conceptual strategies that have recently emerged in the important and exciting field of obesity research. We focus primarily on rational approaches targeting central pathways to create novel antiobesity agents, based on fundamental insights into the basic mechanisms regulating body weight. The few medications currently approved for obesity therapy and those marketed for other indications but incidentally discovered to promote weight loss are reviewed elsewhere (3) and will not be discussed here.

	II. Neuroendocrine Regulation of Body Weight

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
Despite marked fluctuations in daily food intake, body weight remains remarkably stable in most humans because overall energy intake and expenditure are exquisitely matched over long periods of time through the process of energy homeostasis (4, 5). In response to alterations of body adiposity, the brain triggers compensatory physiological adaptations that resist weight change. Specifically, weight loss increases hunger and decreases metabolic rate, whereas weight gain elicits the opposite responses (6). Unfortunately for dieters, this homeostatic system defends against weight loss more robustly than against weight gain (7), presumably because it evolved primarily to help animals survive periods of famine, rather than surfeit. The tenacity of the energy regulation system thwarts most attempts at durable weight loss, and, thus far, it has hindered the development of highly effective antiobesity pharmaceuticals. Fortunately, a recent explosion in our understanding of the intricate mechanisms governing this process promises to illuminate molecular targets for new, rationally designed agents that should promote more substantive weight loss.

The status of body energy stores is communicated to the central nervous system by the adiposity-associated hormones leptin, insulin, and possibly selected gastrointestinal (GI) peptides, such as ghrelin (4). Acting in the brain, leptin and, to a lesser extent, insulin decrease food intake and increase energy expenditure, promoting weight loss, and they are thus termed catabolic adiposity signals (Fig. 1). Impinging on the same neuronal targets, ghrelin exerts the opposite effects and is thus an anabolic hormone. Weight loss evokes proportionate decreases in catabolic hormone levels and an increase in ghrelin. These fluxes elicit corresponding alterations in catabolic and anabolic neuropeptides and neurotransmitters in brain centers responsible for energy homeostasis.

View larger version (26K): [in this window] [in a new window]   FIG. 1. Model depicting how changes in body adiposity elicit compensatory alterations in food intake and energy expenditure. Leptin and insulin are adiposity-associated hormones that are secreted in proportion to body fat content. They act in the hypothalamus and other brain sites to stimulate catabolic neural pathways while inhibiting anabolic pathways. This endocrine negative feedback system influences energy balance (the difference between calories ingested and expended) to regulate body adiposity. [Reprinted from M. W. Schwartz et al.: Nature 404:661–671, 2000 (43 ) with permission from Macmillan Publishers Ltd., copyright 2000.]

View larger version (72K): [in this window] [in a new window]   FIG. 2. Hypothalamic targets of circulating adiposity signals. Leptin and insulin act directly through their receptors to stimulate neurons that produce POMC. This precursor protein is cleaved to yield the melanocortin -MSH, a neuropeptide that signals through Mc4r and Mc3r to exert catabolic effects on food intake and energy expenditure. Conversely, leptin and insulin suppress, whereas ghrelin stimulates, activity of adjacent neurons that produce the anabolic neuropeptides NPY and Agrp. Several types of interconnections between NPY/Agrp and POMC cells, involving GABA, Mc3r, and Y1R, ensure that activation of one neuronal type inhibits the other and vice versa. Similarly, Agrp blocks -MSH action by functioning as an inverse agonist of melanocortin receptors. To execute their effects on energy homeostasis, first-order neuronal targets of adiposity signals project from the arcuate nucleus to the paraventricular nucleus, lateral hypothalamic area, and other brain sites. [Reproduced from G. S. Barsh and M. W. Schwartz: Nature Reviews Genetics 3:589–600, 2002, with permission from Macmillan Publishers Ltd., copyright 2002.]

View larger version (44K): [in this window] [in a new window]   FIG. 3. Long-acting adiposity signals and short-acting meal-related signals that contribute to energy balance. Ingested food stimulates gastric distention as well as a set of intestinal peptides that act in unison to cause satiation and promote meal termination, largely signaling through neural connections to the hindbrain. Long-acting adiposity hormones, such as leptin and insulin, augment satiation signals through several mechanisms, including hypothalamus-to-hindbrain pathways, direct actions on hindbrain sites receiving visceral vagal input, and enhancement of vagal responsiveness to relevant gut peptides. Secretion of the orexigenic peptide ghrelin, primarily from the stomach, is stimulated before individual meals and also in response to weight loss. Ghrelin acts on the hypothalamus, hindbrain, vagus nerve, and mesolimbic reward centers to increase food intake and body weight. [Adapted with permission from an illustration by Katharine Sutliff in J. Marx: Science 299:846–849, 2003, from AAAS.]

	III. Principles for the Design of Antiobesity Therapeutics

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
Living organisms obey the first law of thermodynamics, and their body weight depends ultimately upon the balance between energy intake and output. Consequently, three broad strategies to promote weight loss are to stimulate anorexigenic signals, oppose orexigenic signals, or increase energy expenditure, and all of these approaches are under active investigation. In this section, we offer several overarching conceptual principles that could be considered to help prioritize among the myriad of possible specific antiobesity targets. These recommendations represent our personal views, based on our experience in and understanding of the field of body-weight regulation.

First, because the energy homeostasis system is highly redundant, antagonism of anabolic signals is theoretically limited in its ability to promote major weight reduction because changes in other pathways could compensate for the loss of a pure orexigen. On the other hand, pharmacological hyperstimulation of catabolic signals might constitute so indomitable an intervention that no degree of compensation from alternate pathways could offset it.

Second, weight loss resulting from an intervention that only stimulates metabolic rate should elicit an adaptive increase in food intake. Even if the elevation in energy expenditure is so great that it supersedes compensatory hyperphagia, the result would be weight loss occurring at the expense of excessive caloric turnover. Ample evidence from yeast, worms, flies, fish, rodents, and primates demonstrates that long-term caloric restriction increases lifespan, possibly by limiting exposure to reactive oxygen species liberated during fuel metabolism, as well as other mechanisms (9, 10). This phenomenon might raise theoretical concerns that the opposite condition, of chronically elevated energy intake and expenditure, could shorten life span. Pharmacological strategies to increase thermogenesis (by manipulating ß-adrenergic receptors, uncoupling proteins, thyroid deiodinases, etc.) are under investigation, but they have been reviewed elsewhere (11) and are not a focus of this paper.

Third, because body weight is defended by redundant regulatory systems, combination therapies targeting more than one pathway might be required to promote clinically meaningful weight loss. Unfortunately, the Food and Drug Administration (FDA) only approves new agents that are highly effective on their own (12). Thus, there is little motivation for pharmaceutical companies to develop cocktails of multiple novel agents, although such combinations are far more likely to be successful, especially if directed against disparate components of the energy homeostasis system. For example, although as mentioned above, blockade of an orexigenic signal or hyperstimulation of energy expenditure might not prove viable on their own, these approaches could be efficacious when combined with one another or with an anorexigenic compound. Development of such logical drug combinations is discouraged by current regulatory statutes. Fortunately, many endogenous molecules affect more than one aspect of energy homeostasis in a complementary manner; thus, pharmacological manipulation of these signals can simultaneously alter diverse weight-regulatory pathways. For example, some interventions to block the orexigenic hormone ghrelin reduce food intake while also increasing energy expenditure and fat catabolism, and perhaps because of these multifaceted effects, they limit weight gain in adult animals (13). Likewise, the successful weight loss achieved through antagonism of the cannabinoid-1 receptor, which exerts numerous pleiotropic anabolic effects (14), provides a particularly dramatic example of this concept, as detailed in Section VII.

Lastly, the remarkably sophisticated current understanding of adipocyte biology could facilitate development of agents that entirely obliterate fat tissue, and although this might seem intuitively desirable for people with excess adiposity, significant evidence suggests that such approaches would be deleterious. The loss of leptin that accompanies loss of adipose tissue would stimulate food intake, and without a proper tissue repository to accommodate them, ingested lipids would be stored ectopically in liver and muscle, causing severe insulin resistance. The refractory diabetes observed in lean humans with lipodystrophy syndromes and in animals with genetically ablated adipose tissue demonstrates that pharmaceutical attempts to treat obesity by annihilating fat tissue could have dangerous repercussions (15, 16, 17). More moderate approaches directed against adipose tissue could be beneficial, e.g., partial limitation of adipocyte development and/or lipid storage, or amelioration of metabolic syndrome features through inhibition of glucocorticoid production in adipose tissue. For full discussions of the roles played by adipocytes in energy homeostasis, we refer the reader to papers by Handschin and Spiegelman (18) and Trujillo and Scherer (19) in this issue.

	IV. Stimulators of Catabolic Pathways

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
Among the hundreds of genes thought to be involved in energy homeostasis, only a handful are so vital that mutation of them single-handedly causes major disruptions in body weight (20, 21). Interestingly, no single-gene mutation is known to cause wasting, consistent with the notion that systems to defend against weight loss are more robust than those to limit weight gain. Of the 11 known genes that can cause monogenic obesity in humans, at least seven encode catabolic proteins that lie in the leptin-melanocortin circuit [specifically, leptin, leptin receptor, POMC, prohormone convertase 1, melanocortin 3 and 4 receptors, and single-minded 1 (SIM1)] (Fig. 4). Similar findings pertain to spontaneous monogenic obesity genotypes in mice and rats. Thus, compelling experiments of nature identify this pathway as a high-priority target for antiobesity pharmaceuticals.

View larger version (25K): [in this window] [in a new window]   FIG. 4. Indicated in yellow are genes in the leptin-melanocortin pathway that, when mutated, cause monogenic obesity in humans. [Adapted with permission from D. E. Cummings and M. W. Schwartz: Annual Review of Medicine 54:453–471, copyright 2003 by Annual Reviews www.annualreviews.org.]

Theoretically, weight loss achieved by lifestyle modifications or currently available anorectic medications should restore leptin sensitivity, and thereafter leptin treatment might help maintain weight loss. Consistent with this hypothesis, restitution of leptin to baseline levels after diet-induced weight reduction reverses compensatory changes in sympathetic nervous system tone, thyroid hormones, skeletal muscle work efficiency, and total energy expenditure—adaptations that normally accompany weight loss and contribute to weight regain (25). Similarly, tachyphylaxis to anorectic medicines could result from counterregulatory changes in appetite and energy expenditure caused by falling leptin levels, and thus, preventing this decline with low-dose leptin therapy could help maintain drug-induced weight loss. Indeed, reductions in food intake and body weight caused by sibutramine treatment in rats are synergistically enhanced by administration of leptin at low doses, sufficient only to restore circulating leptin to pre-weight loss levels (doses that are ineffective on their own) (26). The prospect that leptin treatment might prove clinically useful to maintain weight loss that has been achieved by more traditional means is an exciting possibility, and further testing of this concept in humans is an important research priority.

B. Strategies to overcome obesity-related leptin resistance
Leptin resistance results from impairments in leptin action at multiple levels, and each of these could theoretically be targeted to overcome leptin insensitivity in obese individuals. First, leptin is normally transported across the blood-brain barrier by a saturable system involving a specialized leptin-receptor isoform, and this transport mechanism is impaired in obesity (27). Recent evidence suggests that intranasal delivery of leptin can overcome this barrier and cause weight loss. Leptin delivered to the nares of rats generated supraphysiological levels in the brain, especially, and importantly, in the hypothalamus. This effect was not diminished when circulating leptin levels were raised by concomitant iv administration (28).

Independent of blood-brain transit, leptin-receptor signaling is blunted in brain areas critical to energy homeostasis in the setting of diet-induced obesity, such that neuronal responsiveness to leptin is diminished even when leptin is injected directly into the brain (29). This problem could be addressed either by creating synthetic leptin-receptor superagonists with even greater signaling strength than the endogenous ligand or by elucidating the intracellular signaling mechanisms engaged by the leptin receptor and devising strategies to enhance these distal pathways. The leptin receptor is a single membrane-spanning class I cytokine receptor with tyrosine kinase activity (30). It is very well characterized, and synthesis of brain-penetrant superagonists is an area of active investigation. It is generally more difficult to create chemical receptor agonists than antagonists, however, and development of synthetic leptin-receptor agonists remains in preclinical stages (31).

Leptin receptor activation engages two intracellular proteins that terminate receptor signaling—namely, suppressor of cytokine signaling-3 (SOCS3) and protein tyrosine phosphatase-1B (PTP1B)—and inhibition of either of these autoinhibitory factors could theoretically increase leptin sensitivity (32, 33, 34). This strategy is particularly compelling for SOCS3 because its activity is increased in obesity, suggesting an etiological role in leptin resistance (35). Reduction in SOCS3 activity by either neuron-specific conditional knockout or heterozygous global knockout increases leptin-induced activation of intracellular signaling events and catabolic neuropeptide expression, with accompanying enhancement of leptin’s weight-reducing effects and resistance to diet-induced obesity (36, 37). Although these observations provide proof-of-principle that SOCS3 is a viable antiobesity drug target, caution is warranted because SOCS3 regulates more than just leptin signaling, and homozygous global knockout mice die in utero (38).

PTP1B inactivates the leptin receptor by dephosphorylating key tyrosine residues that are phosphorylated in response to ligand binding (33, 34). Thus, analogous to SOCS3, inhibition of PTP1B should increase leptin sensitivity. Moreover, because PTP1B also limits insulin-receptor signaling, inhibiting it might increase insulin sensitivity independent of its effects on body weight. Supporting this model and the potential of PTP1B as a target for obesity and diabetes treatment, global and neuron-specific PTP1B knockout mice are lean, resistant to diet-induced obesity, and insulin-sensitive—a phenotype apparently driven more by increased energy expenditure than by decreased food intake (39, 40, 41). As with SOCS3, however, a major challenge in translating these promising findings into clinical utility relates to the difficulty of inhibiting PTP1B selectively in body-weight regulatory circuits because the enzyme is involved in cell cycle regulation, integrin and epidermal growth factor receptor signaling, and responses to cell stresses (41).

C. Second- and higher-order targets of leptin action: melanocortins
Because obesity-related leptin resistance occurs at least partly at the level of leptin gaining access to and activating its first-order neuronal targets in the hypothalamus (e.g., POMC and NPY/Agrp neurons), a logical strategy is to manipulate leptin-regulated pathways distal to these neurons. Of the many such pathways, the leptin-melanocortin system provides particularly appealing targets because of the observation that monogenic obesity phenotypes result from mutations in genes at multiple levels throughout this circuitry (20). [See Fig. 4 and the reviews by Roger Cone (Ref. 42) and I. Sadaf Farooqi and Steven O’Rahilly (21) in this issue.] In addition to activating the melanocortin pathway, leptin also stimulates other second-order hypothalamic anorectic mediators, such as TRH and CRH (43); but these are not very appealing antiobesity drug targets because of their critical roles in thyroid and adrenal regulation, respectively.

In the leptin-melanocortin pathway, POMC is the first key intermediary downstream of leptin-receptor signaling (Fig. 4). Genetic evidence in rodents and humans reveals an indispensable role for this gene product in body-weight regulation (44, 45), and even haploinsufficiency is associated with obesity (46). Pharmacological mechanisms to increase POMC expression are not apparent, however, and even if this could be achieved, it would likely cause undesirable additional effects, given the involvement of POMC-derived peptides in adrenal physiology and other functions. Null mutations in the next component of the pathway, prohormone convertase 1, also cause monogenic obesity in humans (47, 48), and polymorphisms are associated with early-onset obesity (49); but again, this enzyme participates in too many other functions to be a practical drug target. Cleavage of POMC by prohormone convertase 1 produces, among other peptides, -MSH, which activates melanocortin-3 and -4 receptors (Mc3r, Mc4r) to exert catabolic effects (Fig. 4). These receptors are highly promising targets for antiobesity therapeutics because of their vital roles and relative specificity in energy homeostasis, as well as their position downstream of the most well-documented levels of obesity-related leptin resistance.

Ample genetic evidence proves that Mc4r and, to a lesser extent, Mc3r are critical components of the body-weight regulation system. Null mutations in Mc4r cause marked, dominantly inherited monogenic obesity in rodents and humans, associated with increased food intake and decreased energy expenditure (50, 51, 52). Such mutations may account for up to 5% of severe human obesity (53), and even Mc4r haploinsufficiency increases susceptibility to excessive adiposity (54). Genetic ablation of Mc3r in mice causes mild obesity with increased feed efficiency (55, 56), and similarly, inactivating polymorphisms in the human Mc3r gene are associated with pediatric-onset obesity (57). The body-weight perturbations resulting from loss of Mc4r and Mc3r are additive (55), suggesting that agonists activating both receptors might produce greater weight loss than would agents selective for either receptor alone.

Because of the very strong genetic proof that Mc4r signaling is indispensable for normal energy homeostasis, pharmaceutical companies are working to develop small-molecule agonists to this presumably "drugable" G protein-coupled receptor (GPCR), with or without combined Mc3r agonist activity. It was first shown almost a decade ago that food intake in rodents decreases markedly after administration of the melanocortin-receptor agonist melanotan II, whereas it is increased by the melanocortin-receptor antagonist SHU9119 (58). Since that time, many more Mc4r agonists have been developed, including highly potent, enzyme-resistant, long-acting moieties (59). An unexpected additional consequence of Mc4r stimulation was found to be increased penile erections, resulting from both central and peripheral mechanisms. Because such erections might be unsolicited, they can be considered an adverse event resulting from drugs designed to reduce food intake. Difficulties in dissociating the catabolic from the proerectile activities of Mc4r have retarded clinical development of anorexigenic agents in this class. At present, the medical utility of such compounds for weight loss cannot easily be assessed because only very limited preclinical data are available (60). On the other hand, melanocortin-receptor agonists have completed phase I/II trials for the diagnosis and treatment of male erectile dysfunction, and they are scheduled to enter pivotal stage III clinical trials for this indication (61).

Recent evidence has identified SIM1, a transcription factor involved in embryological development of the paraventricular nucleus, as a proximal mediator for the anorectic, but not thermogenic, effects of melanocortins (62) (Fig. 4). As with many other components in the all-important leptin-melanocortin pathway, rodent and human genetic evidence demonstrates that haploinsufficiency or loss of SIM1 causes hyperphagic obesity, as well as resistance to the anorectic effects of melanocortins (63, 64, 65). Conversely, SIM1 overexpression reduces food intake and body weight in mice fed high-fat diets, acting downstream of melanocortin receptors (66, 67). These observations identify SIM1 stimulation as a potential antiobesity strategy, one that is conceptually appealing because it would act even farther downstream of known levels of leptin resistance than melanocortin receptors, although methods to engage SIM1 pharmacologically are not obvious at present.

D. Ciliary neurotrophic factor
Ciliary neurotrophic factor (CNTF) is a glial cell-produced cytokine that exhibits neuroprotective effects and has therefore been explored as a medicine to treat neurodegenerative diseases. Unexpectedly, subjects receiving CNTF in clinical trials for this indication experienced a 10–15% weight loss (68), prompting investigators to consider using CNTF to treat obesity. The exact mechanisms mediating these catabolic effects are unclear, although it is known that they do not result from cachexia or muscle wasting (60). At pharmacological levels, it is conceivable that this cytokine cross-reacts with the cytokine family leptin receptor, a possibility consistent with the observation that CNTF-induced weight loss occurs without a normal compensatory increase in hypothalamic NPY expression, as would also be the case with leptin-induced weight loss (69). However, leptin-receptor signaling is not required for the catabolic actions of CNTF because the peptide still reduces food intake and body weight in leptin-receptor null mice (70). Moreover, unlike leptin, CNTF causes weight loss independent of melanocortins and is effective in mice lacking either POMC or Mc4r (71, 72), both of which are required for leptin’s full anorectic effects. Importantly, CNTF also reduces body weight in animals with leptin resistance resulting from diet-induced obesity (70), suggesting that it might be clinically efficacious in this setting. Although CNTF does not require leptin signaling, its own cytokine receptor, which is expressed in the hypothalamus, has signal transduction elements and activates intracellular signaling pathways similar to those of the leptin receptor (70).

Interestingly, the catabolic effects of CNTF persist long after its administration is discontinued, and recent studies have revealed a probable mechanism to explain this phenomenon. In hypothalamic feeding centers, CNTF induces proliferation of neurons that contain leptin-responsive elements, and chemical inhibition of cell division abrogates the long-term, but not the short-term, effects of CNTF on body weight (73). The implication of these observations is that CNTF might durably increase hypothalamic leptin sensitivity, thereby apparently lowering the defended level of body weight.

Based on these promising scientific findings, CNTF signaling has been targeted in clinical antiobesity studies using axokine, a recombinant human variant of CNTF, modified to increase potency. This sc-injected peptide was tested in a 12-wk, randomized, placebo-controlled, double-blind, multicenter, dose-ranging trial involving 173 obese, nondiabetic participants (74). The optimal dose produced a 4.1-kg weight loss, compared with a 0.1-kg gain in the placebo group. Based on this modestly successful result, a yearlong phase III trial was conducted involving nearly 2000 obese participants. Although the results of that study have not been published, overall the axokine-treated group lost a disappointing 2.9 kg, compared with a loss of 1.1 kg in the placebo group (75). It is likely that this longer trial was less successful than shorter studies because most CNTF-treated volunteers developed anti-CNTF antibodies. A subgroup representing approximately 30% of treated individuals lost considerably more weight, and the magnitude of weight loss correlated negatively with the presence of anti-CNTF antibodies. At present, further development of axokine to treat obesity has been discontinued, based on insufficient efficacy. However, CNTF congeners that do not elicit an immune response, such as chemical peptidomimetics, would theoretically still be reasonable antiobesity drug candidates.

E. Subtype-selective serotonin-receptor agonists
Three of the medicines that have been used clinically to treat obesity—sibutramine, fenfluramine, and dexfenfluramine (d-FEN)—all increase signaling by the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)]. Although the latter two compounds were withdrawn because of cardiac valvulopathy, they were effective weight-reducing agents. Because these drugs are among a very few discovered to date that have been efficacious enough to reach the marketplace, clarifying the exact mechanisms mediating their anorectic actions is a compelling research objective. Such insight could guide the rational development of novel agents that more precisely target the pathways responsible for weight loss, while avoiding undesired side effects resulting from cross-reactivity with other serotonergic pathways.

Serotonin is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes, acting through a family of at least fourteen 5-HT receptor subtypes. Systematic targeted deletion of individual isoforms has identified at least some of the variants that mediate catabolic effects. The first to be implicated in this regard is the 5-HT2C receptor, genetic ablation of which yields mice that develop obesity and related sequelae in midlife as a result of chronic hyperphagia (76, 77). These animals are also refractory to threshold doses of d-FEN (76). A detailed analysis of the mechanism of action of this drug revealed that it directly activates hypothalamic POMC neurons through 5-HT2C receptors that are expressed on a majority of these cells (Fig. 5). Stimulation of POMC neurons subsequently activates Mc3r and Mc4r, and consequently, pharmacological or genetic antagonism of these melanocortin receptors attenuates the anorectic effects of d-FEN (78, 79). In short, d-FEN reduces food intake, at least in part, by activating 5-HT2C receptors on arcuate POMC neurons, thus engaging the same melanocortin pathway that is critical to leptin-mediated anorexia.

View larger version (33K): [in this window] [in a new window]   FIG. 5. Sites of 5-HT action on melanocortin pathways. Acting through 5-HT1B receptors, 5-HT hyperpolarizes and inhibits NPY/Agrp neurons, thereby decreasing GABAergic inhibitory input to POMC cells. 5-HT also directly activates POMC neurons through its effects on 5-HT2C receptors. These processes lead to a reciprocal increase in a-MSH and decrease in Agrp release at melanocortin target sites. [Reprinted from L. K. Heiser et al.: Neuron 51:239–249, copyright 2006, with permission from Elsevier.]

Evidence from a limited number of clinical studies examining the use of isoform-selective 5-HT receptor agonists as anorectic agents appears to confirm that stimulation of 5-HT2C, and possibly 5-HT1B, reduces hunger, food intake, and body weight in humans. In a small double-blind, placebo-controlled trial, the combined 5-HT2C/1B receptor agonist m-chlorophenylpiperazine reduced subjective hunger ratings and caused a subtle (0.75 kg) but significant weight loss over 2 wk in obese individuals (80). Several 5-HT2C-selective agonists are also under development. One such agent was tested in a 12-wk phase IIb randomized, double-blind, placebo-controlled, multicenter trial in 469 obese individuals (81). The optimal dose caused 3.6 kg of weight loss, compared with a loss of 0.3 kg with placebo. Overall, selective serotonin receptor activation represents one of the most clinically advanced antiobesity strategies currently in development.

	V. Inhibitors of Anabolic Neuropeptides

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
A. Neuropeptide Y and its many receptors
In addition to stimulating melanocortins and other catabolic pathways, the adiposity hormones leptin and insulin inhibit anabolic neuropeptides, such as hypothalamic NPY (Fig. 2), and chronic NPY administration powerfully increases food intake and body weight. Thus, pharmacological blockade of NPY signaling is a potential antiobesity strategy. A critical role for NPY in energy homeostasis was challenged by the finding that NPY-knockout mice are not abnormally lean (82). However, crossing these mutants with leptin-deficient mice attenuates the obese ob/ob phenotype (83). This and other observations suggest that although NPY might not be necessary to maintain normal body weight, it is required for the full response to leptin deficiency, which is a model of energy deficit. The clinical implication of this perspective is that blockade of NPY signaling might be most useful at preventing regain of body weight that has been lost by other means. Such an antirecidivism agent could represent a useful adjunct medicine.

NPY is the most abundant central neuropeptide, and its pleiotropic functions make global blockade of NPY signaling an untenable option. However, the peptide acts through at least five GPCR subtypes (Y1, Y2, Y4, Y5, and Y6), so vigorous efforts have been undertaken to identify the specific isoforms responsible for NPY-induced hyperphagia, hoping that at least one of these might be sufficiently restricted to feeding regulation that it could safely be targeted to promote weight loss (84). Initial studies implicated Y1 and Y5 as the most important isoforms for the orexigenic effects of NPY, and selective antagonists to these and other Y-receptor subtypes were developed. Recent incarnations of such reagents have challenged the importance of Y5 in feeding behavior because selective blockade of this receptor fails to impair baseline food intake, NPY-stimulated feeding, and the hyperphagic response that follows a period of fasting (85, 86). Moreover, Y5-knockout mice develop a paradoxical late-onset obesity (87). Y1 is widely expressed in the brain and periphery, and its importance in NPY-related feeding is reasonably well established. Selective Y1 agonists increase food intake and body weight (88, 89), whereas Y1 antagonists block NPY-induced feeding as well as refeeding hyperphagia (84). However, it is not clear that such agents promote meaningful weight loss on their own, and some of their effects on food intake may result indirectly from increased anxiety due to Y1 blockade in the amygdala. Y1-Knockout mice display a blunted refeeding response but are not unusually lean at baseline, and over time, they, like Y5 knockouts, paradoxically develop increased body weight (90). Moreover, although the acute feeding effects of NPY are attenuated in such animals, chronic NPY administration increases food intake and body weight as much in Y1 knockouts as in wild types. The implication of these findings is that other Y-receptor subtypes may contribute to the feeding effects of NPY. Although the mild lean phenotype of Y4-knockout mice might seem to suggest a role for this isoform, that phenotype is not thought to result from hypothalamic mechanisms, so the importance of Y4 in hypothalamic NPY-induced feeding remains uncertain (91). The Y2 receptor is discussed in Section VI.B in relation to peptide YY.

In summary, there is no consensus regarding which Y-receptor subtype is the most important for NPY-induced feeding, and because Y-receptors are generally involved in numerous physiological functions, the difficulty in targeting them for obesity without eliciting unacceptable side effects remains a potentially insurmountable obstacle. Not surprisingly, clinical studies of Y-receptor antagonists for obesity are almost nonexistent after many years of drug development.

B. Melanin-concentrating hormone
Another leptin-inhibited orexigenic hypothalamic neuropeptide is melanin-concentrating hormone (MCH). Exclusively expressed in magnocellular neurons of the lateral hypothalamic area, this peptide acts downstream of at least some levels of leptin resistance, and thus it represents another logical option for obesity pharmacotherapy. Furthermore, both gain- and loss-of-function experiments demonstrate an important role for MCH in body-weight regulation. MCH administration or transgenic overexpression increases body weight by stimulating food intake and adipogenesis, while decreasing energy expenditure (92). Conversely, MCH knockout mice have reduced food intake and elevated metabolic rate, with consequently lowered body weight and adiposity (93). The feeding effects of MCH are mediated by a GPCR, the MCH1 receptor (MCHR1) (94). Although genetic ablation of this receptor also yields a lean phenotype, there are important differences between MCH- and MCHR1-knockout mice. Specifically, MCHR1-deficient animals unexpectedly display increased food intake, apparently in response to leanness that results from markedly elevated locomotor activity and energy expenditure (95).

Medicinal blockade of MCH signaling is being explored as an antiobesity modality. Because this would be achieved with antagonists of MCHR1, mice lacking the MCHR1 gene theoretically represent a better model than MCH knockouts to help predict the impact of such pharmacotherapy. Based on the phenotype of MCHR1-deficient mice (95), one would predict that MCHR1 antagonists will promote weight loss, but a concern is that this effect might be at the expense of chronically elevated energy intake and expenditure. As articulated above under our second general principle of obesity pharmacotherapy, such a situation could be hazardous. Another theoretical concern is that MCH-producing neurons in the lateral hypothalamic area project widely throughout the neuraxis to areas that express MCHR1 and are involved in cognitive, olfactory, motor, and autonomic functions (94). Not surprisingly, therefore, MCH regulates many functions beyond feeding, such as locomotor activity, anxiety, aggression, sensory processing, and learning. Thus, it may be challenging to design anti-MCH agents that selectively modulate energy homeostasis without exerting untoward side effects. On the other hand, some such heterologous effects might prove beneficial because genetic and pharmacological antagonism of MCHR1 reduces indices of anxiety and depression in rodents (94). Early testing of MCHR1 antagonism in humans has begun (96), and it will be exciting to see if this proves to be an effective treatment for obesity and/or mood disorders.

	VI. Gastrointestinal Peptides That Regulate Food Intake

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The gut-brain axis is a pivotal component of appetite regulation, and the GI system offers a rich menu of targets for possible antiobesity therapeutics, in the form of numerous satiation peptides and one orexigenic hormone, ghrelin (Fig. 3). Some of these factors, such as cholecystokinin, can alter meal patterns but not body weight (97), so they do not represent particularly promising targets to promote weight loss. However, pharmacological manipulation of other gut peptides does change body weight, so the pathways in which these molecules act are candidates for obesity treatment. We have very recently reviewed GI peptides and their role in feeding regulation elsewhere in detail (8), and related material is covered by Steven Bloom and colleagues in this issue (98). Consequently, we will not reiterate that information here, except to summarize a few highlights pertaining to selected molecules with particular clinical potential.

A. Glucagon-like peptide-1
Three peptides released from lower intestinal L cells in response to ingested nutrients—glucagon-like peptide-1 (GLP-1), peptide-YY (PYY), and oxyntomodulin—are believed to act in concert with other postprandial GI signals (e.g., gastric distention, cholecystokinin, etc.) to cause satiation, promoting meal termination (8). All three of these L cell products have been shown to decrease food intake and body weight in experimental animals and to exert anorectic effects in humans. Thus, stimulation of each is being explored as potential antiobesity strategy.

The protease-resistant GLP-1 congener exenatide is already marketed to treat diabetes because it increases insulin secretion and possibly sensitivity. In clinical trials, exenatide reduces hemoglobin A1C at least as well as do other oral diabetes agents, while also causing a modest but progressive weight loss that persists for at least 2 yr (99). This is especially remarkable because improvements in glycemic control achieved with other agents typically promote weight gain. The mechanisms mediating anorectic effects of GLP-1 are not fully known but appear to involve an important role for the vagus nerve (8). Although GLP-1 receptor agonists are not currently approved for obesity treatment, the impressive effects of exenatide on body weight would seem to warrant serious consideration of such agents for this indication.

B. Peptide-YY_3-36
Peripheral administration of PYY_3-36 can reduce food intake and body weight in rodents, apparently by activating autoinhibitory Y2 receptors on orexigenic NPY/Agrp neurons in the hypothalamus, and thereby derepressing adjacent anorexigenic POMC neurons (Fig. 2) (100). In addition, recent evidence indicates vagal mediation of a component of PYY_3-36-induced anorexia. Although the catabolic effects of peripheral PYY_3-36 are somewhat subtle and subject to vicissitudes of experimental conditions in rodents (101), these effects may be more robust in primates (102), and PYY_3-36 administration in humans has been reported to lessen hunger and decrease single-meal food intake by 36%, without eliciting illness or subsequent compensatory hyperphagia (103). Importantly, the anorectic efficacy of exogenous PYY_3-36 is fully intact in obese persons, in contradistinction to obesity-associated leptin resistance. These findings set the stage for longer term studies to determine whether chronic administration of PYY_3-36 or related peptidomimetics can promote weight loss. The injectable PYY_3-36 analog AC-162352 was tested in phase I studies, with limited success due to nausea (96). A PYY_3-36 nasal spray yielded mildly promising results among 37 obese participants in a short phase Ic trial, causing 1.3 pounds of weight loss in 6 d (96). If such nasal delivery facilitates PYY_3-36 penetration into the brain, as mentioned above for leptin nasal sprays, then weight loss resulting from this formulation would seem surprising. It would be unexpected because central PYY_3-36 administration powerfully increases food intake, presumably by activating deep-brain orexigenic Y5 receptors, at which PYY_3-36 is also active, rather than by selectively engaging autoinhibitory Y2 receptors on arcuate NPY/Agrp neurons, as circulating PYY_3-36 is hypothesized to do (100).

C. Oxyntomodulin
Oxyntomodulin, a product of the proglucagon gene from which GLP-1 is cleaved, is also secreted from lower intestinal L cells in response to ingested nutrients. In rodents, exogenous administration decreases food intake through GLP-1 receptor-dependent and -independent mechanisms (8). Chronic oxyntomodulin injections in animals decrease body weight more than expected from the reduction in food intake, suggesting an additional effect from increased energy expenditure. In humans, iv oxyntomodulin infusions acutely decrease hunger and single-meal food intake, without reducing food palatability (104). Repeated injections decreased body weight by 0.5 kg/wk more than placebo in a 4-wk human trial (105). Importantly, oxyntomodulin reduced single-meal intake by 25% at the beginning of this study and by 35% at the end, indicating no tachyphylaxis to its anorectic effects over that period. These favorable results provide justification for larger, longer term trials of oxyntomodulin as a potential antiobesity agent. Its crystal structure has recently been solved, and this should facilitate the rational design of orally active peptidomimetics.

D. Amylin
Amylin, a peptide cosecreted with insulin postprandially from pancreatic ß-cells, inhibits gastric emptying, gastric acid output, and glucagon secretion. It can also dose-dependently decrease meal size and food intake, through vagus-independent actions on the hindbrain area postrema. The synthetic amylin analog pramlintide is marketed for diabetes treatment, but it also causes mild progressive weight loss for at least 16 wk in humans (106, 107).

E. Ghrelin
Ghrelin, the only known orexigenic hormone, is released from the stomach and upper intestine shortly before individual meals and is rapidly suppressed by food intake (13). This pattern of secretion, together with other findings, implicates ghrelin in mealtime hunger and meal initiation (108), or at least in preparing physiologically for meals (109). Moreover, ghrelin appears to play a role in long-term body-weight regulation, based on the following observations (13): 1) circulating ghrelin levels display compensatory responses to changes in body weight, rising with weight loss and vice versa; 2) ghrelin enters selected brain areas and acts through its receptor to modulate neuronal activity in classical centers of energy homeostasis—including the hypothalamus, caudal brainstem, and mesolimbic reward nodes—and ghrelin injections in any of these sites potently stimulate food intake; and 3) chronic or repeated ghrelin administration increases body weight in experimental animals and humans through anabolic effects on numerous aspects of energy intake, energy expenditure, and fuel utilization.

The final criterion that ghrelin should fulfill to qualify as a participant in overall energy homeostasis is that chronic blockade of its signaling should decrease body weight. Whether ghrelin satisfies this important criterion has been questioned because congenital deletions of the gene for either ghrelin or its receptor yield very subtle phenotypic disturbances, with mutant mice displaying resistance to high-fat diet-induced obesity but minimal body-weight changes on standard chow (110, 111). However, developmental adaptations to the lifelong absence of ghrelin signaling could engage compensatory neuroendocrine pathways that might mask the true importance of ghrelin in energy homeostasis. Consistent with this possibility, reductions in food intake and body weight have been reported among adult animals subjected to pharmacological blockade of ghrelin signaling by administration of ghrelin-specific antibodies into the brain; high doses of low-potency ghrelin receptor antagonists; anti-ghrelin-receptor antisense oligonucleotides; and immunization against endogenous ghrelin (13, 112). Although the specificity and nontoxicity of these interventions has not been verified universally, there is a substantial compendium of evidence suggesting that blockade of ghrelin signaling in adult animals reduces body weight. An elegant verification of this conclusion was provided with ghrelin-blocking RNA Spiegelmers, stable aptamer nucleotide sequences designed to bind specifically to bioactive ghrelin. Administration of such molecules restrained body weight in rodents, and importantly, treatment was ineffective in ghrelin-knockout mice, as was administration of reverse-sequence Spiegelmers to wild types—findings that validate the ghrelin-based specificity of these agents’ catabolic actions (113).

Together, these observations indicate that ghrelin participates in overall energy homeostasis. Whether its role in this process is sufficiently important that blocking ghrelin signaling, for example with chemical antagonists to its GPCR receptor, will facilitate meaningful weight loss in humans is a key question for future research. Ghrelin levels are low among obese individuals but rise in response to weight loss, apparently as part of a compensatory response that helps promote weight regain. Therefore, as with leptin therapy, the most clinically useful application of ghrelin-receptor blockade might be to prevent weight regain that has been achieved by other means, rather than to initiate weight loss de novo.

	VII. Bringing It All Together: Cannabinoid-1 Receptor Antagonism

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
Among the many novel antiobesity strategies currently under development, pharmacological antagonism of the anabolic cannabinoid-1 receptor will probably be the first to come into clinical use. With large-scale phase III trials of the lead compound, rimonabant, yielding generally favorable results, many European nations have approved this agent, and FDA endorsement in the United States is likely in the near future. It might seem that the success of this approach contradicts features of the first and third general principles of obesity therapeutics that we offered in Section III of this paper, i.e., that blockade of a single orexigenic signal is unlikely to promote major weight loss. However, in this case, these tenets are superseded by elements in the latter part of our third principle articulated above, namely that manipulation of one molecule that influences multiple disparate elements of body-weight regulation could exert a substantial impact. Endocannabinoids exemplify this concept splendidly because they affect virtually every major peripheral and central component of the energy homeostasis system in a concerted manner. By impinging upon the entire network, endocannabinoid blockade should preclude the type of compensatory adaptations that can undermine unipotent interventions.

Products of the marijuana plant, Cannabis sativa, have been imbibed by humans since as long ago as 2600 B.C., when the Chinese Emperor Huang Ti recommended them for pain relief, and the powerful orexigenic effects of cannabis, dubbed "the munchies" by recreational users, have long been known (14). Starting in the 1980s, medical use of cannabinoids has been approved to treat weight loss and anorexia associated with conditions such as AIDS, Alzheimer’s disease, and chemotherapy treatment. Scientific insights into the mechanisms of action of the principal active constituent of cannabis, ⁹-tetrahydrocannabinol, were catapulted forward in 1990 with the cloning of the G protein-coupled cannabinoid-1 receptor (CB1R) (114). Soon thereafter came the identification of natural ligands for CB1R, the lipids anandamide and 2-arachidonoyl glycerol, which are known as endocannabinoids. Also discovered was a related CB2R, which is involved in immune function, whereas CB1R mediates the anabolic effects of exogenous and endogenous cannabinoids (14).

Endocannabinoids modulate neuronal activity through the unique process of retrograde suppression of neurotransmitter release (115). In this process, the action of neurotransmitters on postsynaptic neurons stimulates rapid and transient enzymatic production of endocannabinoids from membrane phospholipid precursors in these cells. Released endocannabinoids then travel backward across the synapse, interact with cannabinoid receptors on presynaptic axons, and in so doing, trigger a variety of intracellular signaling events that inhibit activity of presynaptic neurons. Depending on whether a particular synapse is excitatory (e.g., glutamatergic) or inhibitory (e.g., GABAergic), the presence of an endocannabinoid system in that synapse can either repress or derepress neural transmission through the circuit.

That CB1R might play an important role in body-weight regulation is implied by the fact that it is selectively expressed in virtually every major site in the energy homeostasis system (14). In the brain, CB1R is abundant and widely distributed, including in vital energy-regulatory centers such as the hypothalamus, caudal brainstem, and mesolimbic reward nodes. In the periphery, CB1R is found primarily in the GI tract, adipose tissue, liver, muscle, thyroid, and pancreas—all of which contribute importantly to energy balance. Given this tissue distribution, it is not surprising that CB1R exerts numerous pleiotropic effects on energy and glucose homeostasis, all of which act in concert to promote weight gain and decrease insulin sensitivity. The roster of anabolic and prodiabetic actions of endocannabinoids includes the following: 1) in the hypothalamus, increase of orexigenic and decrease of anorexigenic neuropeptides; 2) in mesolimbic reward centers, enhancement of food palatability and reward reinforcement; 3) in the hindbrain, blunting of nausea and GI satiation signals transmitted from the vagus nerve; 4) in the GI tract, inhibition of satiation signals and potentiation of hunger signals transmitted to vagal sensory nerve terminals, as well as facilitation of nutrient absorption; 5) in adipose tissue and liver, stimulation of lipogenesis; and 6) in muscle, impairment of glucose uptake (14). Consistent with a physiologic role for the endocannabinoid system in energy homeostasis, fasting stimulates it specifically in key centers of body-weight control, including the hypothalamus, hindbrain, mesolimbic reward pathways, and GI tract. Given the protean anabolic actions of CB1R, it is not surprising that pharmacological antagonism of this receptor promotes weight loss.

GPCRs such as CB1R are traditionally amenable to pharmacological antagonism, and indeed, the first small-molecule competitive CB1R antagonist, rimonabant, was created only a few years after the receptor was discovered (116). Since that time, development of rimonabant as an antiobesity medication has proceeded steadily from promising animal studies to advanced clinical antiobesity trials. Through its actions in the hypothalamus, hindbrain, mesolimbic reward centers, and vagus nerve, rimonabant enhances anorexia, potentiates satiation signals, and lessens the motivation to consume palatable, rewarding foods (Fig. 6). Together, these effects reduce food intake and body weight. By also directly inhibiting lipogenesis in adipose tissue, the drug decreases adiposity, complementing the effect of reduced food intake, and it stimulates adiponectin. By enhancing glucose uptake in muscle and impeding de novo lipogenesis in liver, it increases insulin sensitivity, reduces steatosis, and ameliorates dyslipidemia, again complementing the effects of weight reduction on these beneficial parameters (14). This panoply of salutary metabolic effects mirrors the phenotype of CB1R-deficient mice, which are hypophagic, lean, insulin sensitive, and resistant to diet-induced obesity (117, 118).

View larger version (36K): [in this window] [in a new window]   FIG. 6. Major target organs and pharmacological actions through which CB1R antagonists influence food intake, body weight, and metabolism. [Reprinted from U. Pagotto et al.: Endocr Rev 27:73–100, 2006, with permission from The Endocrine Society.]

An important theme conveyed by the RIO trials is that metabolic benefits from rimonabant exceed those expected from the amount of weight lost. Specifically, only approximately half of the increases in insulin sensitivity and high-density lipoprotein cholesterol, as well as the decreases in triglycerides and the overall prevalence of metabolic syndrome, could be accounted for by weight loss. The implication of these findings is that rimonabant exerts advantageous effects on metabolic syndrome pathologies, not only through its ability to promote weight loss but also from other actions, probably including direct effects on adipose tissue, liver, and muscle, as detailed above (Fig. 6).

Rimonabant was generally well tolerated in these trials, causing minor and predictable side effects, including small increases in depressed mood and anxiety, as well as mildly increased nausea compared with placebo. This apparently favorable safety profile may be misleading, however, because volunteers with a history of clinically significant mood disorders were excluded from study. Such disorders are common among obese individuals, and it remains to be seen whether the acceptable side effect profile reported in the trial setting will translate into adequate safety in clinical practice.

Overall, the balance of the safety profile and efficacy for body weight and metabolic parameters observed with rimonabant is at least as good as that seen with any prior weight-reducing medication at this stage in development. Even with this rather exciting agent, however, the amount of weight loss does not break through the frustrating 5–10% barrier that traditionally limits effectiveness of nonsurgical antiobesity interventions. Moreover, it remains to be seen whether the safety and efficacy of rimonabant will persist if it comes into widespread and long-standing clinical usage. Based on principles articulated near the beginning of this paper, it is possible that combining a CB1R antagonist with a compound that pharmacologically hyperstimulates catabolic pathways might yield greater weight loss, and this possibility should be investigated.

	VIII. Closing Comments

Top Abstract I. The Obesity Crisis II. Neuroendocrine Regulation of... III. Principles for the... IV. Stimulators of Catabolic... V. Inhibitors of Anabolic... VI. Gastrointestinal Peptides... VII. Bringing It All... VIII. Closing Comments References

 
As the secrets of the energy homeostasis system continue to be decoded, prospects are bright for the development of novel antiobesity medications that should help facilitate more substantial weight loss than is currently achieved with nonsurgical interventions. In parting, we would like to emphasize that such agents will always be best used in conjunction with lifestyle modifications. Dieting and exercise remain the cornerstones of obesity therapy. However, more effective medicines to augment the impact of these efforts would be welcome among obese individuals as they fight against their energy homeostasis systems. There is good reason for optimism that new classes of such pharmaceutical adjuncts will be available in the foreseeable future.

	Footnotes

 
This work was supported by National Institutes of Health Grants K12 RR023265-03 (to K.E.F.-S.) and RO1 DK61516 and PO1 DK68384 (to D.E.C.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online November 22, 2006

Abbreviations: Agrp, Agouti-related protein; CB1R, cannabinoid-1 receptor; CNTF, ciliary neurotrophic factor; d-FEN, dexfenfluramine; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GPCR, G protein-coupled receptor; 5-HT, 5-hydroxytryptamine; Mc3r, melanocortin-3 receptor; Mc4r, melanocortin-4 receptor; MCH, melanin-concentrating hormone; MCHR1, MCH receptor 1; NPY, neuropeptide Y; POMC, proopiomelanocortin; PTP1B, protein tyrosine phosphatase-1B; PYY, peptide-YY; RIO, Rimonabant in Obesity; SIM1, single-minded 1; SOCS3, suppressor of cytokine signaling-3.

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