Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II.

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.
Authors	Lawrence W Castellani, Peter Gargalovic, Maria Febbraio, Sarada Charugundla, Ming-Len Jien, Aldons J Lusis
Journal	Journal of lipid research (J Lipid Res) Vol. 45 Issue 12 Pg. 2377-87 (Dec 2004) ISSN: 0022-2275 [Print] United States
PMID	15466364 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Apolipoprotein A-II Glycogen
Topics	Animals Apolipoprotein A-II (biosynthesis, genetics) Female Gene Dosage Glycogen (metabolism) Heterozygote Homozygote Insulin Resistance (genetics, physiology) Liver (metabolism) Male Mice Mice, Transgenic Muscle, Skeletal (metabolism)

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