Ghrelin-LEAP2 system dynamically regulates energy balance, appetite, and glucose homeostasis, emerging as a therapeutic target for obesity and T2DM.
Background
The global prevalence of obesity and type 2 diabetes (T2DM) necessitates novel therapeutic strategies. Ghrelin, a gut-derived acylated hormone, is a key regulator of appetite, food reward, and metabolic processes, primarily acting via the growth hormone secretagogue receptor (GHSR). Ghrelin's acylation by ghrelin O-acyltransferase (GOAT) is crucial for its activity. However, the full regulatory landscape of ghrelin signaling, particularly its endogenous antagonists, has remained a critical gap in understanding metabolic homeostasis.
Study Design
This review synthesizes recent findings on the physiological and pathophysiological roles of ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2), focusing on their relevance to obesity and type 2 diabetes. It examines the mechanisms of GHSR activation by acylated ghrelin and the counteracting effects of LEAP2, which has been recently identified as an endogenous antagonist and inverse agonist of GHSR. The review integrates evidence regarding the dynamic interplay between ghrelin and LEAP2 in regulating energy balance, glucose homeostasis, and appetite control, particularly in the context of nutritional status and weight loss.
Results
Emerging evidence consistently 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 underscore the critical role of the ghrelin/LEAP2 ratio as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, influencing metabolic responses to nutritional status and weight loss interventions. The ghrelin-LEAP2 system is recognized as a key regulatory pathway in metabolic homeostasis, representing 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 currently under active investigation. > The ghrelin-LEAP2 ratio functions as a dynamic regulator of energy balance, glucose homeostasis, and appetite control, with reciprocal changes observed in obesity and T2DM.
Key Findings
- LEAP2 is an endogenous antagonist and inverse agonist of
GHSR, counteracting ghrelin signaling. - Obesity and type 2 diabetes are associated with reduced ghrelin and increased LEAP2 levels, especially with insulin resistance.
- The ghrelin/LEAP2 ratio dynamically regulates energy balance, glucose homeostasis, and appetite.
- The ghrelin-LEAP2 system is a promising therapeutic target for obesity and metabolic disorders.
- Pharmacological strategies like ghrelin antagonists, LEAP2 analogues, and
GOATinhibitors are under investigation.
Why It Matters
Understanding the ghrelin-LEAP2 system fundamentally shifts our approach to obesity and type 2 diabetes by identifying a novel, endogenously regulated axis for intervention. This review highlights that targeting the ghrelin-LEAP2 axis could offer new pharmacological strategies beyond traditional appetite suppressants or insulin sensitizers. For peptide users and biohackers, this research points to the potential for future compounds that modulate GHSR activity, either by mimicking ghrelin's effects, enhancing LEAP2's antagonism, or inhibiting ghrelin acylation. While these strategies are still preclinical, they pave the way for a new generation of metabolic therapeutics that could restore metabolic balance by fine-tuning the body's natural hunger and satiety signals.
ghrelin
leap2
obesity
type-2-diabetes
appetite
glucose-homeostasis