Critical Insights into LEAP2 Biology and Physiological Functions: Potential Roles Beyond Ghrelin Antagonism.

Liver-expressed antimicrobial peptide 2 (LEAP2) has recently emerged as a novel hormone that reduces food intake and glycemia by acting through the growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor. This discovery has led to a fundamental reconceptualization of GHSR's functional dynamics, now understood to be under a dual and opposing regulation. LEAP2 exhibits several distinctive features. LEAP2 is released by hepatocytes and enterocytes-two cell types that lack classical regulatory secretory mechanisms and may respond differently to nutrient signals. LEAP2 is also found in higher concentrations in plasma than ghrelin, even under energy-deficit conditions, and modulates GHSR by inhibiting both ghrelin-dependent and ghrelin-independent activities. Given these characteristics, LEAP2 appears to play a major role in regulating GHSR activity in vivo, extending beyond simple ghrelin antagonism and being crucial for the long-term regulation of energy balance. A deeper understanding of how LEAP2 functions may clarify the functional implications of GHSR in different physiological contexts and unlock new therapeutic strategies for treating obesity, diabetes, and other metabolic disorders.