Altered Fatty Acid and Mitochondrial Metabolism in the Liver of Pregnant Adiponectin‐Deficient Mice Contributes to Insulin Resistance and Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a common pregnancy‐related health condition. While genetics, lifestyle and diet contribute to development of GDM, evidence suggests that low levels of adiponectin increases the risk for GDM. Adiponectin is a fat derived hormone that improves the sensitivity of tissues to insulin. We hypothesize that adiponectin deficiency causes fatty liver during pregnancy, ultimately contributing to the development of GDM. Methods We compared the glucose and insulin tolerance of pregnant (3 rd trimester) adiponectin−/− (strain B6;129‐ Adipoq tm1Chan /J) and wild‐type mice, and assessed parameters of hepatic metabolism, including mitochondrial function and fatty acid metabolism. We assessed the impact of adiponectin supplementation by administering adenovirus mediated full length adiponectin at the end of the second trimester of pregnancy, and comparing to control containing GFP. Results In the third trimester, pregnant adiponectin−/− mice exhibited fasting hyperglycemia regardless of diet (9.2mmol/L vs. 7.7mmol/L in controls, p<0.05). These mice display impaired glucose and insulin tolerance relative to wild‐type controls. Pregnant adiponectin−/− mice develop hepatic steatosis, including a 3‐fold elevation in hepatic triglycerides (p<0.05). This was associated with altered hepatic lipid metabolism, including a 2.5 fold increase in fatty acid synthase expression (p<0.05), elevated circulating free fatty acids, triglycerides and cholesterol. Nearly 2‐fold reduction (p<0.05) in maximal mitochondrial respiration was observed via oxidative flux analyzer in hepatocytes of adiponectin −/− mice. Hepatocytes from pregnant adiponectin−/− mice show dramatically reduced respiratory capacity when using fatty acids alone, and display elevated synthesis and secretion of triglycerides and cholesterol. Gestational weight gain and food consumption were similar in knockout and wild‐type mice. Adiponectin supplementation to pregnant adiponectin−/− mice significantly improved glucose tolerance, prevented fasting hyperglycemia, and attenuated fatty liver development. Conclusion Results show that adiponectin deficiency is associated with altered hepatic lipid metabolism and hepatic steatosis during pregnancy. Consequently, adiponectin deficiency contributes to mid‐gestation insulin resistance and hyperglycemia characteristic of GDM. Moreover, adiponectin supplementation rescues the effects of adiponectin deficiency on insulin sensitivity and hepatic lipid metabolism. Support or Funding Information Research Manitoba, Children's Hospital Research Institute of Manitoba