reg3g Modulates Glycosaminoglycan to Drive Sex-Specific β-Cell Adaptations in Offspring of Obese Mice

Background: Children born to mothers with obesity suffer higher risk for type 2 diabetes driven by impaired pancreatic β-cell function. We identified sex-specific differences in β-cell expression of Regenerating islet-derived protein 3 gamma (Reg3g), a ligand for Exostosin-Like Glycosyltransferase 3 (Extl3), which initiates heparan sulfate glycosaminoglycan (HSG) biosynthesis. Female offspring of obese mice (MatOb) exhibited preserved β-cell insulin secretion associated with elevated islet Reg3g, while male counterparts showed no Reg3g upregulation and impaired insulin secretion.

Objectives: To test the hypothesis that Reg3g differentially regulates β-cell function in male and female offspring exposed to maternal obesity, through modulation of HSG biosynthesis.

Design/Methods: We generated pancreas-specific Reg3g knockout (Pdx1-Cre:Reg3gfl/fl) female mice born to control (Con) or MatOb dams to assess the role of Reg3g in female offspring. RNA sequencing of islets from female MatOb mice was performed to identify transcriptional changes in female offspring of Con and MatOb dams. Oxygen consumption rate (OCR) was measured in islets using BaroFuse as a surrogate for mitochondrial function. In parallel, wild-type male Con and MatOb pups were treated with PBS or recombinant Reg3g (rReg). Glucose tolerance tests (GTT) and glucose-stimulated insulin secretion (GSIS) were performed at P21. Islet glycosaminoglycan was assessed via hydrophilic interaction liquid chromatography.

Results: Female MatOb littermate controls (MatOb-LC) exhibited modest glucose intolerance (17% ↑ GTT AUC vs Con-LC*), while Reg3g-deficient MatOb (MatOb-KO) females had significantly worsened glucose intolerance (33% ↑ GTT AUC*) and lower insulin secretion (31% ↓ GSIS*). Islet RNAseq revealed enrichment of mitochondrial gene sets in MatOb-LC and -KO compared to Con, and this was validated by increased OCR. MatOb-LC islets also showed enrichment of heparin binding/aminoglycan biosynthetic process, which were absent in MatOb-KO islets. In male MatOb offspring, rReg treatment improved GTT, enhanced GSIS, and restored islet glycan levels compared to PBS-treated controls.

Conclusions: Our findings show that Reg3g plays a critical role in mediating offspring sex-specific β-cell responses to maternal obesity. In females, Reg3g supports glycosaminoglycan biosynthesis and preserves insulin secretion. In males, exogenous Reg3g improves β-cell function, highlighting its therapeutic potential for mitigating metabolic dysfunction in offspring of mothers with obesity.