Abstract
We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II (apoA-II) exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR. The skeletal muscle appeared to be the insulin-resistant tissue in the apoA-II transgenic mice. We now demonstrate a decrease in FA oxidation in skeletal muscle of apoA-II transgenic mice, consistent with reports that decreased skeletal muscle FA oxidation is associated with increased skeletal muscle triglyceride accumulation, skeletal muscle IR, and obesity. The decrease in FA oxidation is not due to decreased carnitine palmitoyltransferase 1 activity, because oxidation of palmitate and octanoate were similarly decreased. Quantitative RT-PCR analysis of gene expression demonstrated that the decrease in FA oxidation may be explained by a decrease in medium chain acyl-CoA dehydrogenase. We previously demonstrated that HDLs from apoA-II transgenic mice exhibit reduced binding to CD36, a scavenger receptor involved in FA metabolism. However, studies of combined apoA-II transgenic and CD36 knockout mice suggest that the major effects of apoA-II are independent of CD36. Rosiglitazone treatment significantly ameliorated IR in the apoA-II transgenic mice, suggesting that the underlying mechanisms of IR in this animal model may share common features with certain types of human IR.
Highlights
We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR
We previously demonstrated that transgenic mice overexpressing the HDL apolipoprotein, apolipoprotein A-II (apoA-II), exhibit several traits associated with the IR syndrome [12]
We demonstrate that FA oxidation is decreased in the skeletal muscle of the apoA-II transgenic mice, and that this decrease in oxidation is unlikely due to changes in Carnitine palmitoyltransferase 1 (CPT-1), but rather to the step in oxidation catalyzed by medium-chain acyl-CoA dehydrogenase (MCAD)
Summary
We previously demonstrated that transgenic mice overexpressing mouse apolipoprotein A-II (apoA-II) exhibit several traits associated with the insulin resistance (IR) syndrome, including increased atherosclerosis, hypertriglyceridemia, obesity, and IR. We previously demonstrated that HDLs from apoA-II transgenic mice exhibit reduced binding to CD36, a scavenger receptor involved in FA metabolism. Studies using genetically altered mice have demonstrated that both the scavenger receptor CD36 and the HDL-associated protein apolipoprotein A-II (apoA-II) alter FA metabolism and IR [11,12,13,14,15,16]. We placed the apoA-II transgene onto a CD36 knockout background and demonstrated that plasma triglyceride and insulin concentrations are not markedly different in the apoA-II transgenic mice, whether or Abbreviations: apoA-II, apolipoprotein A-II; CPT-1, carnitine palmitoyltransferase 1; FATP-1, fatty acid transport protein 1, We found that IR in apoA-II transgenic mice quickly responds to treatment with rosiglitazone
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