Physiological Increases in Uncoupling Protein 3 Augment Fatty Acid Oxidation and Decrease Reactive Oxygen Species Production Without Uncoupling Respiration in Muscle Cells

Abstract

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...

Upregulation of peroxisome proliferator-activated receptor gamma coactivator gene (PGC1A) during weight loss is related to insulin sensitivity but not to energy expenditure

“…A recent hypothesis on the physiological role of UCP3 could help interpret the decrease in UCP3 expression during weight loss [41]. In fact, based on in vitro experiments, UCP3 has been proposed to be a factor that limits reactive oxygen species (ROS) production by facilitating fatty acid oxidation [41].…”

“…In fact, based on in vitro experiments, UCP3 has been proposed to be a factor that limits reactive oxygen species (ROS) production by facilitating fatty acid oxidation [41]. Thus, the role of UCP3 would be to protect muscle tissue against lipotoxicity, rather than to regulate energy expenditure.…”

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

“…In the present study, overproduction of UCP2 by more than tenfold also decreased insulin secretion. Indeed, there is now evidence in several cell types that a moderate increase in UCP2 [34,39] or UCP3 [40,41] levels does not induce any sign of mitochondrial uncoupling. The results of the present study demonstrate that this could also be the case for pancreatic Fig.…”

Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins

“…UCP2 expression is induced through activation of peroxisome proliferator-activated receptor Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins (PPAR ), which is involved in fatty acid oxidation (Mori et al, 2004). In L6 myotubes, overexpression of UCP3 specifically increases fatty acid oxidation (MacLellan et al, 2005). These findings suggest that UCPs may be involved in the energy homeostasis.…”

“…It is reported that UCP1 is responsible for energy expenditure whereas UCP2 and UCP3 are involved in the fatty acid oxidation Hesselink, 2002, 2004;Hesselink et al, 2003;Sell et al, 2004;MacLellan et al, 2005). Although the primary function of UCP2 and UCP3 is not the regulation of energy metabolism, they seem to influence energy balance metabolism as a secondary effect and may be important in the prevention and/or treatment of obesity.…”