Abstract 17307: Endothelial Nitric Oxide Synthase Promotes a Shift in Adipocyte Phenotype in Diet-Induced Obesity
Obesity and diabetes are the most pressing health issues of our time. Current CDC estimates show that over two-thirds of American adults are overweight or obese and nearly 10% display frank type 2 diabetes. Although a decrease in nitric oxide (NO) bioavailability has been linked to insulin resistance, it is not known how increasing NO affects diet-induced obesity and diabetes. We hypothesized that overexpression of endothelial nitric oxide synthase (eNOS) would mitigate diet-induced obesity and insulin resistance. Mice overexpressing eNOS (eNOSTG) and wild-type C57BL/6 mice (WT) were placed on either 60% high fat or 10% low fat diet for six weeks. The eNOSTG mice showed a striking resistance to diet-induced obesity compared with WT mice, as evidenced by decreased weight gain (4.29±1.04g vs. 9.00±1.52g; n=13, p<0.05), despite nearly identical increases in plasma cholesterol and similar glucose and insulin intolerance. This resistance to obesity was further supported by the differences evident in adipocyte morphology. The mean adipocyte area of the high fat-fed eNOSTG mice was decreased compared with WT mice (1949±461µm2 vs. 4022±249µm2 n=7, p<0.05). Adipose tissue of eNOSTG mice also showed increased mitochondrial content compared with WT mice. Protein levels of the mitochondrial proteins cytochrome c oxidase subunit 1 and aldehyde dehydrogenase 2, as well as PGC1α and Sirt3 were increased by two fold or greater (p<0.05). However, no increase in UCP-1 levels was detected. Extracellular flux analysis of differentiated 3T3 adipocytes treated with an NO donor (DETA-NONOate) showed increases in oxidative phosphorylation, glycolysis, and fatty acid oxidation compared with untreated adipocytes (n=5, p<0.05). The triglyceride content of differentiated 3T3 adipocytes was decreased by nearly half after incubation with NO in culture. These data suggest that overexpression of eNOS prevents diet-induced obesity and promotes a shift in the adipocytes to a previously un-described phenotype characterized by increased mitochondria and fat oxidation capacity.
- © 2011 by American Heart Association, Inc.