SUMMARY Obesity is a key risk factor for Gestational diabetes mellitus (GDM). Due to the obesity epidemic, the prevalence of GDM has reached an alarming level. Most importantly, GDM has many adverse effects on pregnancy outcomes and postpartum maternal and offspring health. Therefore, it is urgent to elucidate the pathological mechanisms of GDM. Adiponectin is an adipocyte-secreted hormone that improves glucose and lipid metabolism. Hypoadiponectinemia before pregnancy and during the first and second trimesters strongly predicts GDM. Our studies from the previous funding period have demonstrated that adiponectin deficiency causes hyperglycemia and other metabolic abnormalities in pregnant mice. Interestingly, our studies revealed that adiponectin controls maternal metabolic adaptation by indirectly increasing β-cell proliferation and insulin production via placental lactogen (PL). However, decreased insulin secretion rates were still observed in size- matched islets from adiponectin gene knockout (Adipoq-/-) dams indicating additional mechanisms are involved besides β-cell proliferation. Extracellular vesicles (EVs) are well-conserved for intercellular and intra-organ communication. Pregnancy robustly increases EV levels in maternal circulation, partially attributed to placental- derived small EVs (psEVs). Consistent with other reports, our preliminary studies observed a stimulative effect of adiponectin on psEVs production. Importantly, psEVs enhanced glucose-induced insulin secretion of cultured islets. These data suggest that adiponectin, psEVs, and PL provide a pathway for fat/placenta/islet intra-organ crosstalk. During the last funding period, our study also identified a crucial role of pancreatic α-cells in maternal metabolic adaptation. Our study demonstrated that pregnancy increases glucagon-like peptide-1 (GLP-1) production from α-cells and then enhances maternal insulin secretion. A significant reduction of pancreatic GLP-1 was detected in Adipoq-/- dams. Notably, conditionally knocking out the adiponectin receptor 1 (AdipoR1) gene in α-cells significantly reduced GLP-1 production and glucose tolerance during pregnancy. Therefore, we hypothesize that adiponectin regulates islet adaptation to pregnancy through both fat/placenta/islet intra-organ crosstalk and intraislet paracrine. We will use genetic mouse models and human placenta and islets to 1) define the role of psEVs in adiponectin-regulated islet adaptation to pregnancy; 2) determine how adiponectin augments maternal insulin production through α-cells. The anticipated success of this project will have a significant impact on the research of maternal metabolic adaptation.