#45 Alterted Hepatic Fatty Acid And Mitochondrial Metabolism Contributes To Development Of Gestational Diabetes Mellitus In Pregnant Adiponectin-Deficient Mice
Brittany Moyce, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Laura K Cole, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Bo Xiang, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Mario A Fonseca, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Christine Doucette, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Grant Hatch, University of Manitoba, Children’s Hospital Research Institute of Manitoba; Vernon Dolinsky, University of Manitoba, Children’s Hospital Research Institute of Manitoba
Gestational diabetes mellitus (GDM) is a common pregnancy-related condition with implications for both maternal and neonatal health. Genetics and lifestyle both contribute to development of GDM, but evidence suggests that low levels of adiponectin increases the risk for GDM. Adiponectin is a fat derived hormone that improves insulin sensitivity. We hypothesize that adiponectin deficiency causes fatty liver during pregnancy, contributing to the development of GDM.
We compared the glucose and insulin tolerance of pregnant (3rd trimester) adiponectin knockout (KO) (strain B6; 129-Adipoqtm1Chan/J) and wild-type mice, and assessed parameters of hepatic metabolism, mitochondrial function and fatty acid metabolism. An adenovirus was administered at the end of the second trimester to increase levels of full length adiponectin in the circulation.
In the third trimester, pregnant adiponectin KO mice exhibited fasting hyperglycemia regardless of diet (9.2mmol/L vs. 7.7mmol/L in controls, p<0.05) as well as impaired glucose and insulin tolerance relative to wild-type controls. Pregnant adiponectin KO mice develop hepatic steatosis, including a 3-fold elevation in hepatic triglycerides (p<0.05). Altered hepatic lipid metabolism, including a 2.5-fold increase in fatty acid synthase expression (p<0.05) was associated with elevated circulating lipids. A 2-fold reduction (p<0.05) in maximal mitochondrial respiration using glucose was measured in hepatocytes of pregnant adiponectin KO mice. When using fatty acids as a substrate, these cells show reduced respiratory capacity and 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 KO mice improved glucose tolerance, prevented fasting hyperglycemia, and attenuated fatty liver development.
diponectin deficiency during pregnancy altered hepatic lipid metabolism and resulted in hepatic steatosis. Consequently, adiponectin deficiency contributed to insulin resistance and hyperglycemia characteristic of GDM. Adiponectin supplementation rescued the effects of adiponectin deficiency on insulin sensitivity and hepatic lipid metabolism.