Binge Eating Driven by the Ghrelin Receptor Itself — Not the Hunger Hormone

The ghrelin receptor (GHSR) in the brain drives binge-like high-fat eating in mice independently of ghrelin itself. Plasma levels of ghrelin and its natural blocker LEAP2 didn't change during binge eating, and injecting ghrelin systemically didn't alter binge behavior. However, blocking the receptor's constitutive (always-on) activity in the brain — using either LEAP2 or a synthetic blocker (K-(D-1-Nal)-FwLL-NH2) delivered directly to the brain — reduced binge-like high-fat intake. Notably, blocking only ghrelin-triggered receptor activity (using [D-Lys3]-GHRP-6 or JMV2959) did not reduce binge eating, confirming it's the receptor's baseline signaling, not ghrelin binding, that drives this behavior.

Animal study using male mice exposed to a 4-day binge-like eating protocol with time-limited access to high-fat diet. Researchers measured plasma ghrelin and LEAP2 levels during binge eating, then tested the effects of systemically or centrally (brain) administered ghrelin, LEAP2, and various GHSR blockers on high-fat intake. They compared blockers that target ghrelin-stimulated receptor activity versus blockers that target the receptor's constitutive (always-on) activity.

This study reveals something surprising: the ghrelin receptor can promote binge eating even without ghrelin. The receptor has its own built-in activity that doesn't require the hunger hormone to turn it on. This means binge eating may be driven by brain receptor activity that circulating hormone levels can't predict or fully explain — which could change how we think about treating binge eating disorder and compulsive overeating.

Binge eating disorder affects millions of people, and current treatments are limited. Most research has focused on ghrelin as the hunger hormone driving overeating, but this study shows the receptor itself may be the real culprit — operating independently of its hormone. This opens a new therapeutic angle: drugs that specifically target the receptor's constitutive activity rather than just blocking ghrelin. It also connects to the emerging understanding of LEAP2 as a natural counter to ghrelin signaling.

This is a mouse study, and binge eating in mice may not fully model human binge eating disorder. Central (brain) administration of drugs is not practical in humans. The 4-day protocol is short-term and may not reflect chronic binge eating patterns. Sample sizes for individual experimental groups are not specified in the abstract. The study does not address what triggers the constitutive GHSR activity or whether it can be modulated long-term.