Leptin

Leptin is a peptide hormone predominantly produced by white adipose tissue. It circulates in the bloodstream and informs the brain about the size of the body's fat stores, helping regulate appetite, energy expenditure, and metabolic homeostasis. Leptin crosses the blood–brain barrier and acts chiefly on leptin receptors in the hypothalamus and related brain regions.

Leptin was identified in 1994 as the product of the ob gene. Loss-of-function mutations in the ob gene or in the leptin receptor (LEPR) cause severe hyperphagia and obesity in humans and mice (ob/ob and db/db models). Circulating leptin levels correlate with fat mass and are modulated by caloric intake, insulin, sex steroids, and inflammation. Fasting lowers leptin, while feeding or nutrient signals raise it.

Mechanistically, leptin binds to LEPR and activates signaling pathways such as JAK–STAT, PI3K, and MAPK. This signaling reduces the activity of the orexigenic neuropeptides NPY and AgRP and increases anorexigenic POMC/CART expression, promoting satiety and increased energy expenditure. In obesity, high circulating leptin is common but signaling is often diminished, a phenomenon known as leptin resistance.

Beyond energy balance, leptin influences reproduction, bone metabolism, immune function, and neuroendocrine regulation. It plays a role in puberty onset and menstrual function, and modulates immune cell activity and inflammatory responses.

Clinical use of leptin is limited. Recombinant leptin (metreleptin) is approved for congenital leptin deficiency and generalized lipodystrophy but is not effective for common obesity. Potential adverse effects include injection-site reactions and immune-related responses. Ongoing research explores leptin’s therapeutic potential in metabolic, inflammatory, and reproductive disorders.