Leptin
Definition
A hormone from fat cells that tells the brain how much energy is stored. It falls during weight loss, raising appetite and lowering energy use, a key driver of weight regain.
Leptin
Leptin is a 167-amino-acid hormone made mainly by white fat tissue. Its blood level roughly tracks total body fat. It was discovered in 1994 as the product of the ob gene, which is mutated in genetically obese mice. Leptin tells the brain about long-term energy stores by acting on receptors in the hypothalamic arcuate nucleus. There it curbs appetite (by reducing NPY/AgRP signaling and increasing POMC signaling) and affects energy use, thyroid function, reproduction and immunity.
Early hopes that leptin would treat obesity were not met. Most people with obesity have high leptin, not low. They have leptin resistance: the hormone is there, but the brain no longer responds properly. Leptin treatment works only in rare cases of true leptin deficiency (a few single-gene obesity syndromes) and in lipodystrophy.
Leptin matters most in modern obesity care for understanding weight regain. As body fat falls during weight loss, leptin falls too, sometimes by more than the fat loss would suggest, so the brain senses an energy shortage even when plenty of fat remains. That drives up appetite, lowers energy use (metabolic adaptation) and creates the well-documented biological pull toward regaining weight after any successful weight loss.
GLP-1-class drugs partly override this leptin-driven pushback during treatment, because they curb appetite through separate brain pathways. The open question, for retatrutide, tirzepatide, semaglutide and CagriSema alike, is what happens when treatment stops. Evidence with semaglutide shows substantial weight regain over about one year off treatment, consistent with leptin-driven biology taking over again once the drug’s appetite suppression is gone.