Dysregulated glucose and fatty acid metabolism in pregnant adiponectin deficient mice contributes to the development of gestational diabetes mellitus
Introduction: Gestational diabetes mellitus (GDM) is a common pregnancy-related condition with implications for both maternal and neonatal health. Adiponectin is a fat derived hormone that improves insulin sensitivity and in pregnant women, low levels of adiponectin are associated with elevated risk for GDM. We hypothesize that adiponectin deficiency causes fatty liver during pregnancy, contributing to the development of GDM.
Methods: We compared the glucose and pyruvate tolerance of pregnant (3rd trimester) adiponectin knockout (KO) (strain B6;129-Adipoqtm1Chan/J) and wild-type (WT) mice, and assessed the regulation of glucose and fatty acid metabolism in the liver. Impact of adiponectin supplementation at the end of the second trimester was measured by administering adenovirus expressing full-length adiponectin and comparing to control containing GFP.
Results: : In the third trimester, fasting pregnant adiponectin KO mice are hyperglycemic (9.2mmol/L vs. 7.7mmol/L in controls, p<0.05) and glucose intolerant relative to WT controls. Adiponectin KO mice have elevated gluconeogenesis (determined by pyruvate tolerance test), which is accompanied by increases of hepatic gluconeogenic genes such as Pck (2-fold, p<0.05) and G6pc (3-fold, p<0.05), which are not responsive to insulin. Pregnant adiponectin KO mice develop hepatic steatosis and a 3-fold (p<0.05) elevation in hepatic triglycerides relative to wild-type. Hepatic fat deposition in adiponectin KO mice is accompanied by a corresponding ~4-fold increase (p<0.05) in Fasn gene expression which is important for fatty acid biosynthesis in the liver. Gestational weight gain and food consumption were similar in KO and wild-type mice. Adenoviral-mediated adiponectin supplementation to pregnant adiponectin KO mice improved glucose tolerance, prevented fasting hyperglycemia, and attenuated fatty liver development.
Conclusion: Adiponectin deficiency during pregnancy contributed to hepatic steatosis and dysregulation of gluconeogenesis and consequent hyperglycemia. Adiponectin supplementation in pregnancy rescues hepatic steatosis and improves glucose tolerance.