Endocrine Reviews Current Issue

Metabolism and Circadian Rhythms--Implications for Obesity

Froy, O. — Fri, 05 Feb 2010 10:00:37 PST

Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Human homeostatic systems have adapted to daily changes in light and dark in a way that the body anticipates the sleep and activity periods. Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei of the anterior hypothalamus that responds to the environmental light-dark cycle. Similar clocks have been found in peripheral tissues, such as the liver, intestine, and adipose tissue, regulating cellular and physiological functions. The circadian clock has been reported to regulate metabolism and energy homeostasis in the liver and other peripheral tissues. This is achieved by mediating the expression and/or activity of certain metabolic enzymes and transport systems. In return, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. In addition, the core clock mechanism has been shown to be linked with lipogenic and adipogenic pathways. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence for the relationship between the circadian clock and metabolic homeostasis. In addition, clinical studies in shift workers and obese patients accentuate the link between the circadian clock and metabolism. This review will focus on the interconnection between the circadian clock and metabolism, with implications for obesity and how the circadian clock is influenced by hormones, nutrients, and timed meals.

The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

Pagel-Langenickel, I., Bao, J., Pang, L., Sack, M. N. — Fri, 05 Feb 2010 10:00:39 PST

Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM.

Small G Proteins in Islet {beta}-Cell Function

Kowluru, A. — Fri, 05 Feb 2010 10:00:39 PST

Glucose-stimulated insulin secretion from the islet β-cell involves a sequence of metabolic events and an interplay between a wide range of signaling pathways leading to the generation of second messengers (e.g., cyclic nucleotides, adenine and guanine nucleotides, soluble lipid messengers) and mobilization of calcium ions. Consequent to the generation of necessary signals, the insulin-laden secretory granules are transported from distal sites to the plasma membrane for fusion and release of their cargo into the circulation. The secretory granule transport underlies precise changes in cytoskeletal architecture involving a well-coordinated cross-talk between various signaling proteins, including small molecular mass GTP-binding proteins (G proteins) and their respective effector proteins. The purpose of this article is to provide an overview of current understanding of the identity of small G proteins (e.g., Cdc42, Rac1, and ARF-6) and their corresponding regulatory factors (e.g., GDP/GTP-exchange factors, GDP-dissociation inhibitors) in the pancreatic β-cell. Plausible mechanisms underlying regulation of these signaling proteins by insulin secretagogues are also discussed. In addition to their positive modulatory roles, certain small G proteins also contribute to the metabolic dysfunction and demise of the islet β-cell seen in in vitro and in vivo models of impaired insulin secretion and diabetes. Emerging evidence also suggests significant insulin secretory abnormalities in small G protein knockout animals, further emphasizing vital roles for these proteins in normal health and function of the islet β-cell. Potential significance of these experimental observations from multiple laboratories and possible avenues for future research in this area of islet research are highlighted.

Sex Steroid Hormones, Hormonal Contraception, and the Immunobiology of Human Immunodeficiency Virus-1 Infection

Hel, Z., Stringer, E., Mestecky, J. — Fri, 05 Feb 2010 10:00:39 PST

Worldwide, an increasing number of women use oral or injectable hormonal contraceptives. However, inadequate information is available to aid women and health care professionals in weighing the potential risks of hormonal contraceptive use in individuals living with HIV-1 or at high risk of infection. Numerous epidemiological studies and challenge studies in a rhesus macaque model suggest that progesterone-based contraceptives increase the risk of HIV-1 infection in humans and simian immunodeficiency virus (SIV) infection in macaques, accelerate disease progression, and increase viral shedding in the genital tract. However, because several other studies in humans have not observed any effect of exogenously administered progesterone on HIV-1 acquisition and disease progression, the issue continues to be a topic of intense research and ongoing discussion. In contrast to progesterone, systemic or intravaginal treatment with estrogen efficiently protects female rhesus macaques against the transmission of SIV, likely by enhancing the natural protective properties of the lower genital tract mucosal tissue. Although the molecular and cellular mechanisms underlying the effect of sex steroid hormones on HIV-1 and SIV acquisition and disease progression are not well understood, progesterone and estrogen are known to regulate a number of immune mechanisms that may exert an effect on retroviral infection. This review summarizes current knowledge of the effects of various types of sex steroid hormones on immune processes involved in the biology of HIV-1 infection.

The Effects of Opioids and Opioid Analogs on Animal and Human Endocrine Systems

Vuong, C., Van Uum, S. H. M., O'Dell, L. E., Lutfy, K., Friedman, T. C. — Fri, 05 Feb 2010 10:00:39 PST

Opioid abuse has increased in the last decade, primarily as a result of increased access to prescription opioids. Physicians are also increasingly administering opioid analgesics for noncancer chronic pain. Thus, knowledge of the long-term consequences of opioid use/abuse has important implications for fully evaluating the clinical usefulness of opioid medications. Many studies have examined the effect of opioids on the endocrine system; however, a systematic review of the endocrine actions of opioids in both humans and animals has, to our knowledge, not been published since 1984. Thus, we reviewed the literature on the effect of opioids on the endocrine system. We included both acute and chronic effects of opioids, with the majority of the studies done on the acute effects although chronic effects are more physiologically relevant. In humans and laboratory animals, opioids generally increase GH and prolactin and decrease LH, testosterone, estradiol, and oxytocin. In humans, opioids increase TSH, whereas in rodents, TSH is decreased. In both rodents and humans, the reports of effects of opioids on arginine vasopressin and ACTH are conflicting. Opioids act preferentially at different receptor sites leading to stimulatory or inhibitory effects on hormone release. Increasing opioid abuse primarily leads to hypogonadism but may also affect the secretion of other pituitary hormones. The potential consequences of hypogonadism include decreased libido and erectile dysfunction in men, oligomenorrhea or amenorrhea in women, and bone loss or infertility in both sexes. Opioids may increase or decrease food intake, depending on the type of opioid and the duration of action. Additionally, opioids may act through the sympathetic nervous system to cause hyperglycemia and impaired insulin secretion. In this review, recent information regarding endocrine disorders among opioid abusers is presented.

Heterozygous Orthodenticle Homeobox 2 Mutations Are Associated with Variable Pituitary Phenotype

Fri, 05 Feb 2010 10:00:39 PST

Identification and In vitro Characterization of Follicle Stimulating Hormone (FSH) Receptor Variants Associated with Abnormal Ovarian Response to FSH

Fri, 05 Feb 2010 10:00:39 PST

Insulin Modulates Food-Related Activity in the Central Nervous System

Fri, 05 Feb 2010 10:00:39 PST

Are There Any Sensitive and Specific Sex Steroid Markers for Polycystic Ovary Syndrome?

Fri, 05 Feb 2010 10:00:39 PST

Growth Hormone (GH) Deficiency Type II: A Novel GH-1 Gene Mutation (GH-R178H) Affecting Secretion and Action

Fri, 05 Feb 2010 10:00:39 PST

Intragenic GNAS Deletion Involving Exon A/B in Pseudohypoparathyroidism Type 1A Resulting in an Apparent Loss of Exon A/B Methylation: Potential for Misdiagnosis of Pseudohypoparathyroidism Type 1B

Fri, 05 Feb 2010 10:00:39 PST

Precursor Cells in Mouse Islets Generate New {beta}-Cells in Vivo during Aging and after Islet Injury

Liu, H., Guz, Y., Kedees, M. H., Winkler, J., Teitelman, G. — Fri, 05 Feb 2010 10:00:39 PST

The TRH Gene Is Regulated by Thyroid Hormone at the Level of Transcription in Vivo

Sugrue, M. L., Vella, K. R., Morales, C., Lopez, M. E., Hollenberg, A. N. — Fri, 05 Feb 2010 10:00:39 PST

Minireview: Delivering the Code: Polyplex Carriers for Deoxyribonucleic Acid and Ribonucleic Acid Interference Therapies

Christie, R. J., Nishiyama, N., Kataoka, K. — Fri, 05 Feb 2010 10:00:39 PST

Minireview: A Tiny Touch: Activation of Cell Signaling Pathways with Magnetic Nanoparticles

Sniadecki, N. J. — Fri, 05 Feb 2010 10:00:39 PST

Thyroid Hormone Antagonizes Tumor Necrosis Factor-{alpha} Signaling in Pituitary Cells through the Induction of Dual Specificity Phosphatase 1

Lasa, M., Gil-Araujo, B., Palafox, M., Aranda, A. — Fri, 05 Feb 2010 10:00:39 PST

Sustained Activity of the EGF Receptor Is an Absolute Requisite for LH-Induced Oocyte Maturation and Cumulus Expansion

Reizel, Y., Elbaz, J., Dekel, N. — Fri, 05 Feb 2010 10:00:39 PST

Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation

Fri, 05 Feb 2010 10:00:39 PST