Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents

Area of Science:

• Neuroendocrinology
• Molecular Biology
• Obesity Research

Background:

• Alpha-melanocyte-stimulating hormone (alpha-MSH) is a key anorexigenic neuromodulator.
• The processing and inactivation of alpha-MSH are not fully understood, limiting therapeutic strategies for obesity.
• Enzymatic control of alpha-MSH activity is crucial for understanding its role in weight regulation.

Purpose of the Study:

• To investigate the enzymatic inactivation of alpha-melanocyte-stimulating hormone (alpha-MSH).
• To identify the enzyme responsible for alpha-MSH inactivation and its role in body weight maintenance.
• To explore the therapeutic potential of targeting this enzyme for obesity treatment.

Main Methods:

• Generation and analysis of a subcongenic mouse strain with reduced body fat.
• Positional cloning to identify candidate genes, including prolylcarboxypeptidase (PRCP).
• Real-time PCR, biochemical assays with recombinant PRCP, and administration of PRCP inhibitors.

Main Results:

• Prolylcarboxypeptidase (PRCP) was identified as an enzyme that inactivates alpha-MSH1-13 by removing its C-terminal amino acid, producing non-neuroactive alpha-MSH1-12.
• PRCP is expressed in hypothalamic neurons projecting to areas of alpha-MSH release.
• Inhibition of PRCP reduced food intake in wild-type and obese mice.
• Prcp-null mice exhibited elevated hypothalamic alpha-MSH1-13, reduced body fat, and resistance to diet-induced obesity.

Conclusions:

• PRCP plays a significant role in controlling active alpha-MSH levels.
• PRCP is a key regulator of melanocortin signaling and body weight maintenance.
• Targeting PRCP activity offers a potential therapeutic strategy for managing obesity.