GPRC5B preserves a mature β cell state in obesity by controlling MafA expression
Tianpeng Wang, … , Stefan Günther, Nina Wettschureck
Tianpeng Wang, … , Stefan Günther, Nina Wettschureck
Published September 4, 2025
Citation Information: JCI Insight. 2025;10(20):e194115. https://doi.org/10.1172/jci.insight.194115.
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Research Article Endocrinology Metabolism

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

Abstract

In vitro studies have implicated orphan receptor GPRC5B in β cell survival, proliferation, and insulin secretion, but its relevance for glucose homeostasis in vivo is largely unknown. Using tamoxifen-inducible, β cell–specific GPRC5B-KO mice (Ins-G5b–KOs), we show here that loss of GPRC5B does not affect β cell function in the lean state but results in strongly reduced insulin secretion and disturbed glucose tolerance in mice subjected to high-fat diet for 16 weeks. Flow cytometry and single-cell expression analyses in islets from obese mice show a reduced β cell abundance and a less mature β cell phenotype in Ins-G5b–KOs. Expression of β cell–specific transcription factor MafA is reduced both on the RNA and protein level, as are transcripts of MafA target genes. Mechanistically, we show that phosphorylation of cAMP response element-binding protein (CREB), a major regulator of MafA expression, is reduced in islets of obese Ins-G5b–KOs, and we show that this phenotype precedes the downregulation of MafA and MafA target genes. Taken together, GPRC5B helps to maintain mature β cell function in obesity through cAMP/CREB-dependent regulation of MafA expression.

Authors

Tianpeng Wang, Remy Bonnavion, Janett Piesker, Stefan Günther, Nina Wettschureck

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Figure 1

General characterization of tamoxifen-inducible, β cell–specific GPRC5B-KO mice (Ins-G5b–KOs).

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General characterization of tamoxifen-inducible, β cell–specific GPRC5B-...
(A) Gprc5b KO efficiency was determined by qPCR in pancreatic β cells from control and Ins-G5b–KOs that had been bred to a Cre-dependent reporter line to allow β cell isolation by flow cytometry (n = 4/4 mice). (B) Blood glucose levels in control and Ins-G5b–KO mice after 6 hours of fasting (n = 12/13 mice). (C–E) Blood glucose levels (C and D) and insulin levels (E) in control and Ins-G5b–KOs after oral (C) or i.p. (D and E) application of glucose (C, n = 12/12 mice, D, n = 12/12 mice, E, n = 12/12 mice). (F) mRNA-Seq in flow cytometry–isolated β cells harvested from control and Ins-G5b–KO mice that had been bred to a Cre-dependent reporter line to allow β cell isolation by flow cytometry (n = 3/2 mice). The y axis represents DESeq2 normalized counts. (G) Islet viability was determined by lactate dehydrogenase (LDH) cytotoxicity kit after 24 hours of incubation in the absence or presence of a cytokine cocktail (100 ng/mL IL-1β, 125 ng/mL TNF-α, and 125 ng/mL INF-γ) in culture media. Data are presented as absorbance (Abs) values (n = 5/4 mice). Data are mean ± SEM; comparisons between control and KO samples were performed using unpaired Student’s t test (A and B; 2-way repeated measures ANOVA with Šidák’s multiple-comparison test (C–E); multiple unpaired Student’s t test with 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli (F); or 2-way ANOVA with Šidák’s multiple-comparison test (G). ***P ≤ 0.001.