Decreased uncoupling protein (UCP)3 is associated with insulin resistance in muscle of pre-diabetic and diabetic individuals, but the function of UCP3 remains unclear. Our goal was to elucidate mechanisms underlying the negative correlation between UCP3 and insulin resistance in muscle. We determined effects of physiologic UCP3 overexpression on glucose and fatty acid oxidation and on mitochondrial uncoupling and reactive oxygen species (ROS) production in L6 muscle cells. An adenoviral construct caused a 2.2-to 2.5-fold increase in UCP3 protein. Palmitate oxidation was increased in muscle cells incubated under normoglycemic or hyperglycemic conditions, whereas adenoviral green fluorescent protein infection or chronic low doses of the uncoupler dinitrophenol had no effect. Increased UCP3 did not affect glucose oxidation, whereas dinitrophenol and insulin treatments caused increases. Basal oxygen consumption, assessed in situ using self-referencing microelectrodes, was not significantly affected, whereas dinitrophenol caused increases. Mitochondrial membrane potential was decreased by dinitrophenol but was not affected by increased UCP3 expression. Finally, mitochondrial ROS production decreased significantly with increased UCP3 expression. Results are consistent with UCP3 functioning to facilitate fatty acid oxidation and minimize ROS production. As impaired fatty acid metabolism and ROS handling are important precursors in muscular insulin resistance, UCP3 is an important therapeutic target in type 2 diabetes. Diabetes 54: 2343-2350, 2005 I nsulin resistance in muscle is a primary component of type 2 diabetes, a disease with a prevalence that is increasing at an alarming rate in modern society. The importance of mitochondrial oxidative phosphorylation in the development of type 2 diabetes has recently been demonstrated through gene expression profiling studies in muscle of pre-diabetic, diabetic, and nondiabetic populations. Individuals with type 2 diabetes were shown to have reduced expression of genes for key proteins in oxidative metabolism and mitochondrial function in muscle (1). Furthermore, pre-diabetic individuals with insulin resistance but normal glucose tolerance display the same pattern of decreased expression of genes related to mitochondrial oxidative metabolism, consistent with the possibility that such characteristics are directly relevant to the origins and development of type 2 diabetes (2).One of the mitochondrial proteins having decreased mRNA expression in pre-diabetic and diabetic subjects is uncoupling protein (UCP)3 (2). Not only are the levels of mRNA for UCP3 decreased but also are the levels of UCP3 protein. Schrauwen et al. (3) demonstrated decreased UCP3 protein in vastus lateralis of type 2 diabetic patients and no significant association between UCP3 protein and BMI of patients.Mitochondrial UCPs belong to a large family of anion carrier proteins that facilitate the exchange of substrates across the mitochondrial inner membrane. Members of this family play essential roles in the t...

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