Objectives

G protein-coupled receptor 180 (GPR180) has been implicated in systemic energy metabolism, primarily in adipose tissue and the liver. Given impaired whole-body glucose tolerance following GPR180 dysfunction, we aimed to determine whether GPR180 regulates pancreatic β-cell function. We investigated whether GPR180 contributes to β-cell insulin secretion by modulating metabolic processes that couple glucose sensing to mitochondrial energy production.

Methods

Phenotyping of whole-body (Gpr180 ^−/−) and β cell-specific Gpr180 (bGpr180-KO) knockout mice was combined with gain- and loss-of-function studies in MIN6 cells. Glucose-stimulated insulin secretion, pancreatic endocrine architecture and identity, transcriptomic and metabolic profiles, as well as mitochondrial function were assessed using in vivo and in vitro approaches, including metabolic challenge tests, histology, RNA sequencing, targeted metabolomics, respirometry, and transmission electron microscopy.

Results

Loss of GPR180 impaired first-phase insulin secretion and glucose tolerance without affecting insulin sensitivity. These defects were β-cell-autonomous, as confirmed in the bGpr180-KO mice and in MIN6 cells. Functional studies revealed that GPR180 regulates mitochondrial substrate utilization, anaplerotic support of the TCA cycle, and ATP generation without affecting glucose uptake or mitochondrial biogenesis. In particular, Gpr180-deficient β cells showed mitochondrial membrane depolarization, reduced oxygen consumption, and endoplasmic reticulum remodeling, altering the local mitochondrial microenvironment. In vivo, Gpr180 deletion in β cells led to downregulation of mitochondrial gene programs in islets, along with altered endocrine cell identity.

Conclusions

GPR180 is a previously unrecognized regulator of pancreatic β-cell metabolic competence and identity, linking defects in insulin secretion with alterations in mitochondrial function and endocrine cell identity.