Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications


Leptin is an adipocyte-secreted hormone with a key role in energy homeostasis. Studies in animal models, in humans with congenital complete leptin deficiency, and observational and interventional studies in humans with relative leptin deficiency (lower than normal leptin levels) have all indicated that leptin regulates multiple physiological functions, primarily in states of energy deficiency. This information led to proof-of-concept clinical trials involving leptin administration to individuals with relative or complete leptin deficiency. These conditions include congenital complete leptin deficiency, due to mutations in the leptin gene, and states of relative leptin deficiency including lipoatrophy and some forms of hypothalamic amenorrhea. Leptin, in replacement doses, normalizes neuroendocrine, metabolic and immune function in patients with these conditions, but further clinical studies are required to determine its long-term efficacy and safety. Management of leptin-deficient states with replacement doses of leptin holds promise as a therapeutic option. In addition, elucidation of the mechanisms underlying leptin resistance, which characterizes hyperleptinemic states such as human obesity and diabetes, might provide novel therapeutic targets for these prevalent clinical problems.

Key Points

  • The main action of leptin is to regulate multiple physiological functions in states of energy deficiency

  • Common forms of human obesity are characterized by leptin resistance; the mechanisms of this resistance are unknown

  • Leptin therapy is useful in complete congenital leptin deficiency and might be useful in the management of states of relative leptin deficiency, such as hypothalamic amenorrhea and lipodystrophy

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Figure 1: The downstream effects of leptin deficiency and excess


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This work was supported by NIH Grant DK-58785. CS Mantzoros is supported by a Bessel Award from the Alexander von Humboldt Foundation.

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Correspondence to Christos S Mantzoros.

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Christos S Mantzoros has received grant support for clinical research projects from Amgen Inc.

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