LEAP2

LEAP2 was originally identified as a liver-expressed antimicrobial peptide with structural homology to hepcidin. Its function in metabolic regulation remained unknown until Ge et al. (2018) demonstrated in Cell Metabolism that LEAP2 is a potent endogenous antagonist of GHSR1a — the ghrelin receptor — fundamentally reshaping the understanding of hunger regulation as a two-signal system rather than relying on ghrelin alone.

Produced primarily by the liver and small intestine, circulating LEAP2 levels are inversely proportional to ghrelin: they rise in the fed/postprandial state and decline with fasting or caloric restriction. This dynamic makes LEAP2 a natural brake on appetite — counterbalancing ghrelin's hunger-promoting and GH-releasing signals. The system operates in balance: when food is available, LEAP2 rises to suppress appetite and limit GH pulses; during starvation, LEAP2 falls, allowing ghrelin to drive hunger and GH-mediated fat mobilization.

Critically, this balance is disrupted in obesity. Obese individuals show elevated LEAP2 relative to ghrelin — interpreted as a compensatory response to chronic positive energy balance — yet ghrelin signaling persists, suggesting receptor desensitization or pathway adaptation. After bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy), LEAP2 levels rise sharply relative to ghrelin, contributing to the sustained appetite suppression observed post-surgery. This positions the LEAP2:ghrelin ratio as a powerful biomarker and potential pharmacological target.

The minimal active fragment LEAP2[1-14] (the N-terminal 14 amino acids) retains full GHSR1a binding and antagonist activity, enabling peptide truncation strategies for therapeutic development. Research is preclinical-to-early-clinical; no approved pharmaceutical applications exist as of 2025.

// GHSR1a COMPETITIVE ANTAGONISM

LEAP2 binds the orthosteric binding site of the ghrelin receptor (GHSR1a) with nanomolar affinity, directly competing with acylated ghrelin for receptor occupancy. Unlike a simple competitive antagonist, LEAP2 also exhibits inverse agonist activity — reducing the constitutive (ligand-independent) basal signaling of GHSR1a, which is among the highest of any known GPCR (~50% constitutive activity). This dual competitive/inverse-agonist profile produces appetite suppression even in the absence of circulating ghrelin.

// APPETITE AND HUNGER SUPPRESSION

By blocking ghrelin-GHSR1a signaling in the hypothalamic arcuate nucleus (ARC), LEAP2 suppresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) release — the primary orexigenic neuropeptides. Simultaneously, it reduces inhibition of pro-opiomelanocortin (POMC) neurons, shifting the hypothalamic balance toward satiety. Rodent studies demonstrate that exogenous LEAP2[1-14] administration significantly reduces fasting-induced food intake without affecting baseline locomotion or anxiety.

// GH PULSE ATTENUATION

Ghrelin is the primary stimulus for pulsatile GH release from the pituitary. By antagonizing GHSR1a at the pituitary level, LEAP2 attenuates ghrelin-induced GH secretion. This represents a physiological brake on GH-driven lipolysis during fasting — when the body would otherwise aggressively mobilize fat stores. In obesity, where GH pulsatility is already blunted, LEAP2 modulation of this axis may contribute to the disturbed GH/IGF-1 axis observed in metabolic disease.

// FED-STATE METABOLIC SIGNALING

LEAP2 expression and secretion are upregulated by glucose, insulin, and dietary fat in hepatocytes and enterocytes — making it a bona fide nutrient-sensing signal that communicates caloric sufficiency to central appetite circuits. Its post-meal surge mirrors and reinforces GLP-1 and PYY satiety signaling, suggesting LEAP2 is an underappreciated component of the enteroendocrine satiety axis.

Discovery (Ge et al., Cell Metabolism 2018): LEAP2 was identified by unbiased screening of endogenous GHSR1a ligands. The paper demonstrated that LEAP2 circulates in inverse proportion to ghrelin in mice and humans, blocks ghrelin-induced feeding and GH secretion, and that LEAP2[1-14] retains full receptor antagonism — establishing it as the first known endogenous ghrelin receptor antagonist.

M'Kadmi et al. (J Med Chem 2019) characterized LEAP2 as an inverse agonist (not merely competitive antagonist), showing it reduces GHSR1a constitutive activity. This has significant implications for appetite regulation independent of circulating ghrelin levels.

Obesity and bariatric surgery data: Multiple groups have shown the LEAP2:acyl-ghrelin ratio is elevated in obesity and rises further after bariatric surgery — correlating with post-surgical appetite reduction independent of caloric restriction. The LEAP2:ghrelin ratio may be a more informative biomarker than either peptide alone.

Therapeutic development: LEAP2[1-14] is being investigated as a template for GHSR1a antagonists as anti-obesity agents. Stability modifications (N-methylation, D-amino acid substitutions) are active areas of development. No IND filings or clinical trials for exogenous LEAP2 administration have been published as of 2025.

Caloric restriction effect: Unlike most hunger-promoting mechanisms, LEAP2 levels fall sharply during caloric restriction and fasting — suggesting that dietary interventions reduce appetite partly by increasing ghrelin sensitivity (via reduced LEAP2). This may explain why rebound hunger after weight loss is so powerful: ghrelin rises AND LEAP2 falls simultaneously.