LEAP-2

LEAP-2 (Liver-Expressed Antimicrobial Peptide 2) represents one of the most significant recent discoveries in hunger and metabolic biology. Originally identified in 2003 as a member of the antimicrobial peptide family based on its liver expression and structural characteristics (a disulphide-bonded hepcidin-like fold), LEAP-2 was reclassified in 2018 following the landmark study by Ge and colleagues demonstrating it is a potent endogenous antagonist at the ghrelin receptor GHSR1a.

The ghrelin axis - comprising the 28-amino acid acylated peptide ghrelin (the "hunger hormone") and its receptor GHSR1a - is one of the most important regulators of food intake, GH secretion, and metabolic homeostasis. Ghrelin is the only known circulating peptide that stimulates appetite and GH release simultaneously. It was assumed until 2018 that GHSR1a was regulated exclusively by ghrelin agonism, with no endogenous antagonist identified. The discovery that LEAP-2 is present in circulation at concentrations comparable to ghrelin, specifically binds GHSR1a with high affinity, and blocks ghrelin-stimulated signalling completely revised the conceptual framework of ghrelin physiology.

The evidence that LEAP-2 functions as a physiologically relevant ghrelin antagonist is compelling. Plasma LEAP-2 concentrations are inversely regulated compared to ghrelin: while ghrelin rises during fasting and falls after meals, LEAP-2 rises after feeding and falls during prolonged fasting. This reciprocal regulation suggests LEAP-2 serves as part of the "off switch" for hunger signalling after meals, complementing the established suppression of ghrelin by nutrients. Further, mice with genetic LEAP-2 deletion show increased ghrelin sensitivity and altered feeding behaviour consistent with loss of an endogenous brake on ghrelin action.

The relationship between LEAP-2, obesity, and ghrelin resistance is particularly important for metabolic disease research. In contrast to the expected findings in obese individuals (in whom ghrelin should be low due to energy surplus), LEAP-2 levels are paradoxically elevated in obesity - significantly higher than in lean individuals. This LEAP-2 elevation may contribute to the documented phenomenon of "ghrelin resistance" in obese patients, where the normal meal-to-meal ghrelin suppression of appetite appears blunted. Understanding LEAP-2 regulation in obesity may explain why the ghrelin-hunger relationship is disrupted in metabolic disease.

The antimicrobial properties that originally defined LEAP-2 as a family member appear to be genuine but secondary to its role as a metabolic regulator. Like other beta-defensin-like peptides, LEAP-2 has been shown to have antimicrobial activity against some bacterial strains in vitro, and its expression is upregulated by liver injury and inflammatory signals. However, the concentrations required for antimicrobial activity in vitro are substantially higher than circulating plasma concentrations, raising questions about the physiological relevance of its antimicrobial function compared to its hormonal role.

The therapeutic implications of LEAP-2 for obesity treatment are actively being explored. If exogenous LEAP-2 or stable analogues can block ghrelin-mediated food intake in obese individuals, it could represent a novel approach to appetite suppression that works through the body's natural ghrelin regulation pathway rather than through direct CNS manipulation. Early preclinical results are encouraging: LEAP-2 administration in obese mice reduces body weight by suppressing ghrelin-mediated feeding without the nausea and GI effects of GLP-1 agonists. The challenge is developing LEAP-2 analogues with better pharmacokinetic profiles than the native peptide's 30-minute half-life.