Leptin secreted by adipocytes is transported across the blood-brain barrier. Fasting or loss of body fat mass lowers serum and CSF leptin concentrations.

The arcuate nucleus (ARC) is rich in leptin (and insulin) receptors.

Leptin inhibits neuropeptide Y (NPY) and agouti-related protein (ARGP) neurones in the ARC, whose axons project to the lateral hypothalamus (LH) and the paraventricular neucleus (PVN). Both NPY and ARGP are potent orexigenic agents.

Leptin activates pro-opiomelanocortin (POMC) neurones that produce α melanocyte stimulating hormone (αMSH). αMSH acts at the malanocortin-4 (MC4) receptors and is co-expressed with the cocaine and amphetamine-regulated transcript (CART). POMC/CART neurones also project to the LH and PVN and there is a reciprocal innervation from these nuclei to the ARC. Both αMSH and CART are potent anorexigenic agents

The nucleus of the tractus solitarius (NTS) is involved in the termination of food intake, termed satiation. Afferent inputs related to satiety include neurological signals from the vagus and sympathetic systems together with chemical signals such as the endocrine factor from the gut cholecystokinin. There are reciprocal connections between hypothalamic nuclei including the PVN and the NTS.

Obesity is associated with high circulating leptin concentrations. This has given rise to the idea that obesity is a condition marked by leptin (and insulin) resistance.