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Critical Insights Into LEAP2 Biology and Physiological Functions: Potential Roles Beyond Ghrelin Antagonism
1Grupo de Neurofisiología, Instituto Multidisciplinario de Biología Celular (IMBICE) (Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de La Plata, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires), La Plata, Buenos Aires 1900, Argentina.
Endocrinology
|January 17, 2025
Summary
Liver-expressed antimicrobial peptide 2 (LEAP2) is a novel hormone regulating appetite and blood sugar via the ghrelin receptor (GHSR). This discovery reveals dual GHSR regulation, impacting energy balance and metabolic disorders.
Area of Science:
- Endocrinology
- Metabolic research
- Molecular biology
Background:
- The growth hormone secretagogue receptor (GHSR), primarily known as the ghrelin receptor, plays a key role in regulating energy homeostasis.
- LEAP2, a liver-expressed antimicrobial peptide, has been identified as a novel endogenous ligand for GHSR.
- GHSR's function was previously thought to be primarily regulated by ghrelin.
Purpose of the Study:
- To investigate the role of LEAP2 as a novel hormone modulating GHSR activity.
- To understand the dual and opposing regulation of GHSR by LEAP2 and ghrelin.
- To explore the therapeutic potential of targeting the LEAP2-GHSR axis for metabolic disorders.
Main Methods:
- Analysis of LEAP2 expression and secretion from hepatocytes and enterocytes.
- Measurement of plasma LEAP2 concentrations under various physiological conditions.
- In vivo studies to assess the effects of LEAP2 on GHSR activity, food intake, and glycemia.
- Pharmacological characterization of LEAP2's interaction with GHSR, including its effects on ghrelin-dependent and independent pathways.
Main Results:
- LEAP2 is secreted by hepatocytes and enterocytes, which may have unique nutrient-sensing mechanisms.
- Plasma LEAP2 concentrations are higher than ghrelin, even during energy deficit.
- LEAP2 inhibits both ghrelin-dependent and ghrelin-independent GHSR activities.
- LEAP2 reduces food intake and improves glycemia, acting as a crucial regulator of GHSR.
Conclusions:
- LEAP2 represents a novel hormonal regulator of GHSR, distinct from ghrelin.
- The dual regulation of GHSR by LEAP2 and ghrelin offers new insights into energy balance control.
- Understanding LEAP2's function is vital for developing therapeutic strategies for obesity, diabetes, and metabolic diseases.
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