Project Summary/Abstract Annually, over one million newborns are born to obese mothers in the US and suffer a higher risk of developing type 2 diabetes at a younger age. The development of type 2 diabetes (T2D) in the offspring of obese mothers is secondary to a combination of insulin resistance, increased adiposity, increased inflammation, and decreased β cell function. Using preclinical models of maternal obesity, we and others have shown that male offspring are more likely to develop islet insulin secretory dysfunction compared to female offspring. However, the underlying molecular processes remain unclear. Our preliminary data also showed that the sex-differences in glucose intolerance and islet dysfunction correlated with differential expression of Regenerating islet derived protein 3-Gamma (Reg3g). Reg3g is a ligand to Exostosin-Like Glycosyltransferase 3 (EXTL3) that initiates heparan sulfate glycosaminoglycan (HSG) polymerization. Specifically, we found that female offspring exposed to maternal obesity exhibited higher islet Reg3g HSG, and were protected from glucose intolerance and islet dysfunction. The protection was diminished in Reg3g haploinsufficient female offspring. In contrast, male offspring born to obese dams had unchanged islet Reg3g and HSG, and exhibited significantly worse glucose tolerance and a decrease in ex-vivo insulin secretion. Finally, treatment with recombinant Reg3g and a heparan sulfate analogue improved glucose tolerance in male offspring of obese mice. Our preliminary data also implicated ERK1/2 signaling as the downstream pathway activated by Reg3g and HSG that maintains β cell insulin secretion. Given these findings, we hypothesize that the upregulation of Reg3g induces HSG formation and protects offspring of obese mice from β cell dysfunction by maintaining ERK1/2 phosphorylation. We also hypothesize that Reg3g preserves islet insulin secretion in offspring of obese mice and in human islets through HSG polymerization. In this proposal, we will 1) define the role of Reg3g-HSG-ERK1/2 signaling in mediating sex-differences in islet insulin secretion in the offspring of obese mice, and 2) determine the therapeutic potential of Reg3g-mediated HSG polymerization in rescuing pancreatic islet dysfunction in offspring of obese mice and in human islets. This research plan will inform novel and amenable molecular pathways that regulate sex-differences in islet dysfunction in offspring of obese mothers. This career development award also allows the principal investigator to receive training in the state-of-the-art concepts of islet biology and laboratory skills necessary to become an independent physician scientist.