The Ghrelin-LEAP2 System in Obesity and Diabetes: Pathophysiological Roles and Therapeutic Potential

Ghrelin is a gut-derived acylated hormone that regulates appetite, food reward-related behaviours, glycaemic control, and lipid metabolism. These actions are primarily mediated through activation of the growth hormone secretagogue receptor (GHSR), which is highly expressed in the brain and also present in key metabolic organs. Ghrelin acylation by ghrelin O-acyltransferase (GOAT) is required for receptor binding and biological activity. This review examines the physiological and pathophysiological roles of ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), with particular emphasis on its relevance to obesity and type 2 diabetes.

LEAP2 has recently been identified as an endogenous antagonist and inverse agonist of GHSR that counteracts ghrelin signalling. Emerging evidence indicates that obesity and type 2 diabetes are generally associated with reduced circulating ghrelin levels and increased LEAP2 concentrations, particularly in the presence of insulin resistance. These reciprocal changes support the concept that the ghrelin/LEAP2 ratio functions as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, and may influence metabolic responses to nutritional status and weight loss. The ghrelin-LEAP2 system represents a key regulatory pathway in metabolic homeostasis and a promising therapeutic target for obesity and related metabolic disorders. Pharmacological strategies targeting this axis, including ghrelin antagonists, LEAP2 analogues, GOAT inhibitors, and GHSR inverse agonists, are under active investigation, although further studies are required to establish their long-term efficacy and safety.