Noland RC, Woodlief TL, Whitfield BR, Manning SM, Evans JR, Dudek RW, Lust RM, Cortright RN. Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance. somal 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

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... 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 ϳ50% 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 (CO 2 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 EXCESS LIPID ACCUMULATION is implicated in the pathophysiology of obesity-associated insulin resistance, and many believe this is secondary to impairments in lipid disposal pathways (22, 38, 48, 52, 55, 56) . Consequently, much research has focused on primary aspects involved in lipid metabolism, such as mitochondrial oxidative capacity, lipid transport, and lipid trafficking. However, an important factor that has largely been overlooked with respect to maintaining a healthy cellular lipid environment is the peroxisome. Peroxisomes are ubiquitously expressed and have a wide range of cellular functions, including a primary role in fatty acid oxidation (68). Unlike mitochondria, peroxisomal ␤-oxidation is incomplete and cannot chain-shorten fatty acids beyond six carbon residues (50), thus leaving a medium-chain acyl-CoA derivative as well as acetyl-Address for reprint requests and other correspondence: R. N.