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From Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Note: Drs. T. Kelesidis, I. Kelesidis, and Chou contributed equally to this article.
Grant Support: By the National Institute of Diabetes and Digestive and Kidney Diseases (grants DK58785, DK 79929, and DK 81913). Dr. Mantzoros received grant support from Amgen through the Beth Israel Deaconess Medical Center and has been using leptin provided by Amylin Pharmaceuticals for investigator-initiated studies.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M06-2476.
Requests for Single Reprints: Christos S. Mantzoros, MD, DSc, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816, Boston, MA 02215; e-mail, email@example.com.
Current Author Addresses: Drs. T. Kelesidis, I. Kelesidis, Chou, and Mantzoros: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816, Boston, MA 02215.
Author Contributions: Conception and design: C.S. Mantzoros.
Analysis and interpretation of the data: T. Kelesidis, I. Kelesidis, C.S. Mantzoros.
Drafting of the article: T. Kelesidis, I. Kelesidis, S. Chou, C.S. Mantzoros.
Critical revision of the article for important intellectual content: T. Kelesidis, I. Kelesidis, S. Chou, C.S. Mantzoros.
Final approval of the article: I. Kelesidis, S. Chou, C.S. Mantzoros.
Provision of study materials or patients: T. Kelesidis, C.S. Mantzoros.
Statistical expertise: T. Kelesidis, C.S. Mantzoros.
Obtaining of funding: C.S. Mantzoros.
Administrative, technical, or logistic support: I. Kelesidis, C.S. Mantzoros.
Collection and assembly of data: T. Kelesidis, C.S. Mantzoros.
Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital deficiency are obese, and treatment with leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of leptin. Recent studies suggest that leptin is physiologically more important as an indicator of energy deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of leptin in weight-loss management because persons who have recently lost weight have relative leptin deficiency that may drive them to regain weight. Leptin deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of leptin continue to grow and will hopefully soon be used therapeutically.
States of energy excess are associated with hyperleptinemia, but the hypothalamus is resistant or tolerant to the effects of increased leptin (dashed line). Energy deficiency results in hypoleptinemia. As a result, a complex neural circuit comprising orexigenic and anorexigenic signals is activated to increase food intake (17). There is increased expression of orexigenic neuropeptides: AgRP and NPY in the ARC (23) and orexin and MCH in the LHA. Furthermore, there is decreased expression of anorexigenic neuropeptides: POMC and CART in the ARC (23) and BDNF in the VMH. In addition to neurons that project from the LHA to the VTA, leptin also acts at the VTA of the mesolimbic dopamine system to regulate motivation for and reward of feeding. Leptin activation of the NTS of the brainstem also contributes to satiety. In addition, leptin has direct and/or downstream effects on the PVN and PO that are important for neuroendocrine responses to energy deprivation, including decreasing reproductive and thyroid hormones. For the sake of comparison, leptin acts only indirectly on the GnRH-secreting neurons in the hypothalamus, and it can act directly and indirectly on TRH-secreting neurons (17). The effect of leptin on cortisol levels during starvation differs in mice and humans. Unlike in normal mice (24), leptin administration does not reverse the elevated adrenocorticotropin levels associated with starvation in humans (7). The mechanism of leptin's effect on the growth hormone axis is unclear. AgRP = agouti-related protein; ARC = arcuate nucleus; BDNF = brain-derived neurotrophic factor; CART = cocaine- and amphetamine-regulated transcript; CRH = corticotropin-releasing hormone; GnRH = gonadotropin-releasing hormone; IGF-I = insulin-like growth factor I; LHA = lateral hypothalamic area; MCH = melanin-concentrating hormone; NPY = neuropeptide Y; NTS = nucleus of the solitary tract; PO = preoptic area; POMC = proopiomelanocortin; PVN = paraventricular nucleus; TRH = thyrotropin-releasing hormone; VMH = ventromedial hypothalamic nucleus; VTA = ventral tegmental area.
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