GPRC5B preserves a mature β cell state in obesity by controlling MafA expression

Area of Science:

• Endocrinology
• Metabolism
• Molecular Biology

Background:

• In vitro studies suggest orphan receptor GPRC5B influences pancreatic beta-cell survival, proliferation, and insulin secretion.
• The in vivo role of GPRC5B in glucose homeostasis remains largely uncharacterized.

Purpose of the Study:

• To investigate the in vivo function of GPRC5B in pancreatic beta-cells concerning glucose metabolism and homeostasis.
• To elucidate the molecular mechanisms by which GPRC5B impacts beta-cell function, particularly under obesogenic conditions.

Main Methods:

• Generation and utilization of tamoxifen-inducible, beta-cell-specific GPRC5B knockout mice (Ins-G5b-KOs).
• Assessment of glucose tolerance and insulin secretion in lean and high-fat diet-fed mice.
• Flow cytometry and single-cell expression analyses of pancreatic islets.
• Quantitative analysis of MafA expression and its target genes.
• Investigation of cAMP response element-binding protein (CREB) phosphorylation.

Main Results:

• Loss of GPRC5B did not affect beta-cell function in lean mice.
• High-fat diet-induced obesity in Ins-G5b-KOs led to significantly reduced insulin secretion and impaired glucose tolerance.
• Obese Ins-G5b-KOs exhibited reduced beta-cell abundance and a less mature beta-cell phenotype.
• Expression of MafA and its target genes was downregulated in islets of obese Ins-G5b-KOs.
• Reduced CREB phosphorylation in islets of obese Ins-G5b-KOs preceded MafA downregulation, indicating a mechanistic link.

Conclusions:

• GPRC5B plays a critical role in maintaining beta-cell function and glucose homeostasis during obesity.
• GPRC5B preserves beta-cell maturity and insulin secretion in obesity through a cAMP/CREB-dependent regulation of MafA expression.
• Targeting GPRC5B may offer a therapeutic strategy for managing obesity-related metabolic dysfunction.