Central leptin pathways in metabolic homeostasis

Obesity continues to be a major global health crisis, contributing to the rising prevalence of metabolic disorders such as type 2 diabetes, cardiovascular disease, and certain cancers. Central to the regulation of energy homeostasis is the adipocyte-derived hormone leptin, which serves as a key afferent signal to the central nervous system to suppress food intake, enhance energy expenditure, and maintain glucose balance. Since its discovery over three decades ago, a wealth of research has illuminated the molecular, cellular, and physiological mechanisms through which leptin exerts its metabolic effects. These foundational studies have delineated the neural circuits, particularly within the hypothalamus and brainstem, that integrate leptin signaling to co-ordinate complex metabolic responses. This review provides a comprehensive synthesis of the current understanding of leptin’s metabolic actions, with an emphasis on the intracellular signaling cascades that mediate leptin receptor activation. We also highlight the diverse neuronal populations and brain regions that contribute to leptin’s regulatory roles.