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- Title
In Vivo Hepatic Fat Metabolism in the Development of the Zucker Diabetic Fatty Phenotype.
- Authors
Satapati, Santhosh; He, Tianteng; Merritt, Matthew E.; Wertz, Kristen; Esser, Victoria; Burgess, Shawn C.
- Abstract
The Zucker diabetic fatty (ZDF) rat is a well studied model of obesity and Type 2 Diabetes Mellitus. These animals become insulin resistant early on and frankly diabetic by 12 weeks after birth. Adipocyte resistance to the antilipolytic activity of insulin, results in an elevated concentration of circulating free fatty acids in ZDF rats while hepatic insulin resistance leads to inappropriate rates of glucose production. Nonetheless, hepatocytes from these rats maintain elevated rates of de novo lipogenesis and a 3-fold decrease in fat oxidation and this has been implicated as a mechanism for the development of hepatic steatosis in the ZDF rat. However, it is not known 1) how these in vitro results translate to in vivo hepatic metabolism in the ZDF rat; 2) how abnormal hepatic fat oxidation progresses during the advancement of the phenotype or; 3) how obvious disruptions of hepatic energy metabolism integrate with the known disruption of hepatic glucose metabolism. To study these points we administered a stable isotope cocktail containing [sup 13]C-acetoacetate, [sup 13]C-β-hydroxybutyrate, [U-[sup 13]C]propionate and D[sub 2]O in conscious unrestrained ZDF[sup +/+] and their heterozygous littermate controls at 12 and 20 weeks of age. Isotopomer analysis of plasma metabolites by [sup 13]C and [sup 2]H NMR was used to determine in vivo hepatic ketone production, gluconeogenesis, glycogenolysis, pyruvate cycling and TCA cycle flux. The rate of in vivo ketone dilution was suppressed by 50% in the ZDF[sup +/+] rats compared to controls at 12 wks of age suggesting impaired hepatic fat oxidation. Surprisingly, after 20 weeks, the rate of ketone dilution returned to near normal levels despite an obvious worsening of the diabetic phenotype. These results indicate a clear role for impaired hepatic fat oxidation during the early phenotype of these animals, but suggest a more complex adaptation of hepatic fat oxidation during the progression of the diabetic phenotype. ADA-Funded Research
- Subjects
FAT; LIPID metabolism; PEOPLE with diabetes; LABORATORY rats; DIABETES; FAT cells; INSULIN
- Publication
Diabetes, 2007, Vol 56, pA395
- ISSN
0012-1797
- Publication type
Article