Reg3g Supports Mitochondrial and β-Cell Function in Female Offspring of Obese Dams

Abstract

Background and Hypothesis: Maternal obesity (MatOb) is increasingly prevalent, and prior data show that offspring face elevated risks of obesity, insulin resistance, and type 2 diabetes (T2D). These adverse outcomes are more pronounced in male offspring, who show greater impairments in glucose tolerance and insulin secretion. Animal studies reveal that these sex-specific differences are detectable as early as postnatal day 21 (P21), prior to puberty and weaning, suggesting mechanisms independent of sex hormones. We hypothesized that the pancreatic protein, Reg3g, is a key mediator of these sex-specific differences and plays a protective role in regulating islet function in female offspring of obese dams. Methods: In this study, we generated pancreas-specific Reg3g knockout mice by crossing Pdx-Cre+ sires with Reg3gfl/+ dams on chow (Control) or western diet (TD88137) to test whether deletion of Reg3g abolishes sex-differences in metabolic dysfunction in MatOb offspring. Metabolic phenotyping of transgenic offspring, RNA-sequencing, and pathway enrichment analysis was also performed. Results: Metabolic phenotyping revealed that loss of Reg3g impaired glucose tolerance and insulin secretion in offspring of obese dams. At P21, female MatOb offspring exhibited elevated Reg3g expression in both islets and serum. Pathway enrichment analysis further showed that Reg3g- expressing islets from these females had significant enhancement of mitochondrial pathways, including upregulation of Complex I genes involved in energy metabolism and glucose- stimulated insulin secretion (GSIS). In Reg3g absent islets, stress and immune-related pathways were upregulated. Conclusion and Potential Impact: Our findings suggest that Reg3g plays a sex-specific role in maintaining islet function in the offspring of obese dams, likely by supporting mitochondrial metabolic reprogramming in response to metabolic stress. Given the rising prevalence of maternal obesity, identifying Reg3g as a protective factor may help guide future therapeutic strategies to reduce early-life programming of type 2 diabetes risk.