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.

Lipodystrophy is a medical condition characterized by complete or partial loss of adipose tissue. Not infrequently, lipodystrophy occurs in combination with pathological accumulation of adipose tissue at distinct anatomical sites. Patients with lipodystrophy suffer from numerous metabolic complications, indicating the importance of adipose tissue as an active endocrine organ. Not only does the total amount but also the appropriate distribution of fat deposits contribute to the metabolic state. Recent genetic and molecular research has improved our understanding of the mechanisms underlying lipodystrophy. Circulating levels of hormones secreted by adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subsets of patients with lipodystrophy, rationalizing the use of such hormones or agents that increase their circulating levels, such as peroxisome proliferator-activated receptor gamma (PPARγ) agonists, in a subset of patients with lipodystrophy. Other novel therapeutic approaches, including the use of growth hormone (GH) and GH-releasing factors, are also being studied as potential additions to the therapeutic armamentarium. Insights from recent research efforts and clinical trials could potentially revolutionize the treatment of this difficult-to-treat condition.

Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent “proof of concept” clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.

Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.H ypothalamic amenorrhea (HA) is characterized by cessation of menstrual cycles because of dysfunction of the hypothalamicpituitary-gonadal axis, abnormalities in gonadotropin pulsatility, and subsequent estrogen deficiency. This disorder is associated with chronic energy deficiency, usually caused by strenuous exercise, stress, and/or reduced food intake, and accounts for more than 30% of cases of amenorrhea in women of reproductive age (1). In addition to infertility, HA is associated with other neuroendocrine abnormalities, including dysfunction of the thyroid, growth hormone, and adrenal axes (2-7) as well as bone loss (8, 9) and propensity for fractures.Circulating leptin levels reflect the amount of energy stores in fat as well as acute changes in energy intake (10). Hypoleptinemia, signaling a state of energy deficiency, may mediate the changes in the neuroendocrine axes observed in HA. We first showed that acutely depriving mice and then healthy men of energy by caloric restriction resulted in relative leptin deficiency and neuroendocrine abnormalities affecting the gonadal and thyroid axes, and these abnormalities were prevented with recombinant methionyl human leptin (metreleptin) replacement (11,12). Women with HA are chronically energy deficient and, in observational studies, have low leptin levels and loss of diurnal leptin variation (13-16). In our proof-of-concept, open-label pilot study, we administered metreleptin s.c. for 3 mo to normalize leptin levels in women with HA and found that metreleptin treatment resulted in ovulatory menses and significant increases in levels of luteinizing hormone (LH), estradiol, insulin-like growth factor-1 (IGF1), thyroid hormones, and bone formation markers (17). O...