Ghrelin Receptor Mutations and Human Obesity

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• The growth hormone secretagogue receptor (GHSR) was initially identified as an orphan receptor.
• GHSR was later identified as the receptor for ghrelin, a stomach-derived peptide hormone, and is also known as the ghrelin receptor.
• Beyond growth hormone secretion, the ghrelin receptor influences appetite, energy balance, metabolism, cardiovascular function, and immune responses.

Purpose of the Study:

• To investigate the role of naturally occurring mutations in the growth hormone secretagogue receptor (GHSR).
• To understand the functional consequences of GHSR mutations associated with human obesity and short stature.
• To explore potential therapeutic strategies for correcting GHSR mutant defects.

Main Methods:

• Analysis of human genetic studies identifying rare GHSR mutations and single nucleotide polymorphisms across diverse populations.
• Functional characterization of mutant GHSRs to assess cell surface expression, ligand binding, and signaling pathways.
• Evaluation of potential therapeutic interventions, such as pharmacological chaperones and novel ligands.

Main Results:

• Rare GHSR mutations and single nucleotide polymorphisms have been identified in human populations worldwide.
• Functional analyses revealed defects in cell surface expression, ghrelin binding, and signaling in mutant GHSRs.
• These findings link GHSR genetic variations to conditions like human obesity and short stature.

Conclusions:

• Naturally occurring GHSR mutations can lead to significant functional impairments.
• Understanding these mutations provides insights into the receptor's physiological roles.
• Targeting GHSR mutants with specific therapies holds promise for treating associated metabolic and growth disorders.