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Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance

¹Department of Physiology, ²Department of Exercise and Sport Science, and ³Department of Anatomy and Cell Biology, East Carolina University, Greenville, North Carolina

Submitted 7 August 2006 ; accepted in final form 16 July 2007

Peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. This is of potential clinical importance because reduced fatty acid oxidation is suspected to promote excess lipid accumulation in obesity-associated insulin resistance. Our purpose was to assess peroxisomal contributions to mitochondrial oxidation in mixed gastrocnemius (MG), liver, and left ventricle (LV) homogenates from lean and fatty (fa/fa) Zucker rats. Results indicate that complete mitochondrial oxidation (CO₂ production) using various lipid substrates was increased approximately twofold in MG, unaltered in LV, and diminished 50% in liver of fa/fa rats. In isolated mitochondria, malonyl-CoA inhibited CO₂ production from palmitate 78%, whereas adding isolated peroxisomes reduced inhibition to 21%. These data demonstrate that peroxisomal products may enter mitochondria independently of CPT I, thus providing a route to maintain lipid disposal under conditions where malonyl-CoA levels are elevated, such as in insulin-resistant tissues. Peroxisomal metabolism of lignoceric acid in fa/fa rats was elevated in both liver and MG (LV unaltered), but peroxisomal product distribution varied. A threefold elevation in incomplete oxidation was solely responsible for increased hepatic peroxisomal oxidation (CO₂ unaltered). Alternatively, only CO₂ was detected in MG, indicating that peroxisomal products were exclusively partitioned to mitochondria for complete lipid disposal. These data suggest tissue-specific destinations for peroxisome-derived products and emphasize a potential role for peroxisomes in skeletal muscle lipid metabolism in the obese, insulin-resistant state.

fatty acid; lipid metabolism; liver; heart; skeletal muscle; Zucker rat

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