Lisa Bevilacqua

SirT1 Regulates Energy Metabolism and Response to Caloric Restriction in Mice

The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.

The energetic implications of uncoupling protein-3 in skeletal muscle

Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak.

Oxidative status of muscle is determined by p107 regulation of PGC-1α

p107, a member of the retinoblastoma susceptibility protein family, influences lipid metabolism in muscle and other tissues by repressing the PPAR-γ co-factor PGC-1α.