Leptin physiology and pathophysiology in energy homeostasis, immune function, neuroendocrine regulation and bone health

Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.