SKELETAL MUSCLE HETEROGENEITY IN FASTING-INDUCED UPREGULATION OF UNCOUPLING PROTEIN HOMOLOGUES UCP2, UCP3 AND KEY REGULATORS OF LIPID OXIDATION

Samec S, Seydoux J and Dulloo AG
Institute of Physiology, University of Fribourg, Rue du Musée, CH-1700 Fribourg, Switzerland and Department of Physiology, Faculty of Medicine, University of Geneva, Switzerland

Skeletal muscle shows considerable plasticity in its efficiency of fuel utilization and in its preference for glucose or lipids as fuel substrate in response to diet, and is hence believed to be a major site for the regulation of thermogenesis and substrate metabolism. The underlying molecular mechanisms are unknown, but functional studies following the cloning of two new members of the mitochondrial carrier protein family, UCP2 and UCP3, have led us to propose that these could be candidate genes for the regulation of lipids as fuel substrate. At the epicenter of this was the observation that during fasting, both UCP2 and UCP3 gene expressions are upregulated in skeletal muscles, and that the degree of such gene upregulations are much more pronounced in fast-twitch glycolytic than in the slow-twitch oxidative muscles.
Within the context of this hypothesis, we report here studies in the rat which indicate that this muscle-type dependency in UCP regulation at the transcriptional level is closely associated with changes in gene expressions of carnitine palmitoyltransferase I (CPT-1) and medium-chain acyl-CoA dehydrogenase (MCAD), two key enzymes regulating lipid flux across the mitochondrial b -oxidation pathway. Furthermore, the muscle-type dependency in the associations between fasting-induced transcriptional changes in UCP2, UCP3, CPT-1 and MCAD persists when the increase circulating levels of FFA during fasting is abolished by the anti-lipolytic agent nicotinic acid; with blunted responses in slow-oxidative muscle contrasting with unabated increases in their gene expressions in fast-glycolytic muscle.
These studies suggest common regulatory mechanisms, albeit muscle-type specific, for the induction of UCP2, UCP3, CPT-1 and MCAD mRNAs and also revealed that during fasting, the surge in FFA in the circulation may not be a major afferent signal that initiate events leading to the upregulation of UCP homologues and key enzymes regulating lipid oxidation in the fast glycolytic muscles. Further insights into the link between adipose stores metabolism and skeletal muscle genes implicated in substrate metabolism will have major implications for our understanding of metabolic susceptibility to obesity and obesity-related insulin resistance.