ROLE OF LEPTIN IN OBESITY AND TYPE 2 DIABETES: MECHANISMS, CLINICAL EVIDENCE, AND THERAPEUTIC POTENTIAL

Adipocytes are responsible for synthesizing predominantly leptin, a hormone that regulates appetite, energy expenditure, and glucose metabolism. The discovery of leptin in 1994 revolutionized the understanding of systemic energy homeostasis is providing an understanding of obesity and type 2 diabetes mellitus (T2DM) as two connected global health issues. In physiological environments, leptin functions as a satiety signal and metabolic regulator. In obesity and T2DM, however, hyperleptinemia occurs (i. e., elevated levels of leptin) with leptin resistance (i. e., diminished leptin signaling) in which central leptin signaling is impaired regardless of elevated leptin levels. Leptin resistance or malfunction occurring in persons may lose its effects of appetite suppression and metabolic regulation to increase weight gain, insulin resistance, and disruption of glucose homeostasis. The review deals with the molecular structure of leptin, functions, and its mechanism in the pathogenesis of obesity and type II diabetes mellitus (T2DM). It further covers the key pathways such as hypothalamic regulation, hepatic glucose production, muscle metabolism, and function in pancreatic β cells. Moreover, clinical observations are reviewed to highlight the therapeutic potential of leptin-targeted therapies, including leptin sensitizers and combination therapeutics. Although effective in treating rare leptin-deficient disorders, leptin replacement therapy has limited usefulness in treatment of common obesity and type II diabetes mellitus because of widespread resistance. To unlock the potential of leptin therapy, future research needs to be steered toward restoring leptin-sensitivity, leveraging interactions with the microbiome, and the application of precision medicine approaches.