Leptin
Definition
An adipocyte-derived hormone that signals long-term energy stores to the brain. Falls during weight loss, contributing to increased appetite and reduced energy expenditure — a key driver of weight regain.
Leptin
Leptin is a 167-amino-acid hormone produced primarily by white adipose tissue, with circulating concentrations roughly proportional to total body fat mass. It was discovered in 1994 as the product of the ob gene mutated in genetically obese mice. Leptin signals long-term energy stores to the brain by acting on receptors in the hypothalamic arcuate nucleus, where it suppresses appetite (via reduced NPY/AgRP signaling and increased POMC signaling) and modulates energy expenditure, thyroid function, reproductive function, and immune function.
Initial expectations that leptin would be a treatment for obesity were not realized, because most people with obesity have elevated rather than reduced leptin — they exhibit leptin resistance, in which the hormone is present but the brain no longer responds appropriately. Recombinant leptin therapy is effective only in the rare cases of true leptin deficiency (a small number of monogenic obesity syndromes) and in lipodystrophy.
Where leptin matters most in modern obesity care is in understanding weight regain. As body fat decreases during weight loss, leptin concentrations fall — sometimes disproportionately, with the brain perceiving a state of energy deficit even at substantial remaining adiposity. This drives increased appetite, reduced energy expenditure (metabolic adaptation), and the well-documented physiological pressure toward weight regain that follows any successful weight-loss intervention.
GLP-1-class pharmacotherapy partly overrides this leptin-driven counter-regulation during treatment by directly suppressing appetite through independent neural pathways. The open question — relevant for retatrutide, tirzepatide, semaglutide, and CagriSema alike — is what happens when treatment stops. Available evidence with semaglutide suggests substantial weight regain over approximately one year off treatment, consistent with leptin-driven physiology reasserting itself once the pharmacological appetite suppression is removed.