Leptin secreted by adipocytes is transported across the blood-brain barrier to act on specific leptin-sensitive brain sites (yellow circles). In particular, leptin exerts opposite effects on the activity of ARH neurons that produce αMSH and AgRP, two important endogenous ligands of the MC4R (MC4R-dependent pathways appear in red). In response to leptin, these peptides are released in brain sites important in the control of glucose homeostasis, energy expenditure, and feeding within the hypothalamus and brainstem. Recent studies also found that leptin signaling in the VTA and LHA plays a critical role in feeding and reward processes. Finally, different branches of the autonomic nervous system make connections with peripheral tissues (liver, pancreas, etc.) and ultimately mediate leptin actions on peripheral metabolic processes. Overall, leptin modulates the activity of intricate neural circuits that are distributed through many different brain regions. Tg, trigeminal nerve; X, vagus nerve; SNS, sympathetic nervous system; omn, oral masticatory nuclei; rvlm, rostroventral medulla; CeA, central amygdala.