292-OR: High-Fat Diets Containing Sucrose and Fructose, but Not Glucose, Induce Obesity and Hepatic Insulin Resistance via Accumulation of Diacylglycerols

Abstract

Diets high in sugar and fat promote the development of obesity and metabolic complications, while high-sugar, low-fat or high-fat, sugar-free (ketogenic) diets do not. We assessed the importance of sugar in a commonly used 60% high-fat diet (HFD), which contains 6.7% of calories from sucrose. The sucrose content was replaced either with an equal amount of fructose (HFD+RF) or glucose (HFD+RG) and all other components of the diet were identical. After 12 weeks on the diets, the mice on HFD and HFD+RF diets gained more weight, developed hepatic steatosis, glucose intolerance and insulin resistance, compared to the mice on normal chow or HFD+RG diets. A relatively small (6.7%) amount of sucrose or fructose, but not glucose, in a HFD was sufficient to increase the fructolysis (KHK-C, ALDO B and TKFC) and de novo lipogenesis (ME1, ACLY, ACC1, FASN, SCD1) pathways by WB. Metabolomics analysis revealed higher hepatic diacylglycerol (DAG) content in HFD and HFD+RF groups, while HFD+RG group had elevated hepatic triacylglycerol content. Proteomics analysis quantified 3058 unique proteins, 736 of which were significantly different between the mice on chow and HFD. Replacing sucrose with fructose altered only 2 proteins, while replacing sucrose with fructose significantly changed 196 proteins in the liver. Reactome pathway analysis showed that the most altered processes mediate lipid biosynthesis and metabolism. In conclusion, HFDs containing sucrose or fructose but not glucose increase the fructolysis pathway and lead to hepatic DAG accumulation and insulin resistance. Thus, a relatively small amount of fructose, regardless of its source, is sufficient to alter metabolic outcomes in mice consuming a HFD. Disclosure S.Park: None. T.I.Fadhul: None. C.Kahn: None. S.Softic: Research Support; Alnylam Pharmaceuticals, Inc.