SIRT3 Directs Carbon Traffic in Muscle to Promote Glucose Control

The escalating prevalence of the metabolic syndrome has coincided with the emergence of a lifestyle that replaces physical activity with overindulgence. In this setting, excess nutrients continuously bombard the major metabolic organs, leaving resident cells to cope with a steady influx of superfluous carbon fuel. The molecular consequences of energy surplus are far-reaching. Among these, growing evidence suggests carbon overload promotes lysine acetylation, a protein modification prominent in mitochondria and linked to detrimental effects on energy metabolism. Because this phenomenon of carbon stress is increasingly recognized as a key feature of aging and metabolic disease, scientists are now keenly interested in understanding the functional impacts of protein acetylation and the mechanisms that defend against them. The best-characterized countermeasures against protein hyperacetylation are mediated by a family of NAD-dependent deacylases known as the sirtuins, which may have evolved as a stress response mechanism to offset spurious, nonenzymatic acetylation events that occur upon increasing carbon pressure (1). This family of proteins has a wide range of biological effects on disease processes associated with aging, including cancer, neurodegeneration, and metabolic syndrome. Sirtuins remove a variety of posttranslational acyl-modifications from proteins, including acetyl-lysine modifications (2), which accumulate during prolonged high-fat feeding (3,4). Interestingly, within 1 week of feeding mice a fat-rich diet, expression of the mitochondrial sirtuin, SIRT3, increases in the liver (3), possibly to protect against aberrant protein acetylation. Consistent with this prediction, hepatic protein acetylation remains low at this time point. However, after chronic high-fat feeding (13 weeks), SIRT3 expression diminishes and hepatic hyperacetylation of proteins manifests (3). Accordingly, SIRT3 knockout (SIRT3KO) mice are more susceptible to diet-induced acetylation of mitochondrial proteins, which is accompanied by more severe obesity and glucose intolerance relative to their wild-type counterparts. The mechanisms by which SIRT3 deficiency disrupts whole-body glucose homeostasis remain uncertain. In the current issue of Diabetes, Lantier et al. (5) begin to fill this gap by evaluating conscious SIRT3KO mice using the hyperinsulinemic-euglycemic clamp technique—the goldstandard method for measuring insulin sensitivity and glucose flux in vivo. They found that the major contributor to glucose intolerance in high-fat–fed SIRT3KO mice was impaired glucose uptake in skeletal muscle, which appeared to develop without an overt reduction in insulin signaling. The article by Lantier et al. extends previous findings by pinpointing the skeletal muscle as a principal site at which SIRT3 exerts control of glucose metabolism. Furthermore, the study attributes the poor glucose uptake in muscles of SIRT3KO mice to perturbations in the location and activity of hexokinase II (HKII), the irreversible enzyme that phosphorylates and thereby traps glucose within the myocyte. Previous work by this group and others has shown that HKII translocation to the mitochondria and its binding to the voltage-dependent anion channel (VDAC) promote enzyme activity as well as glucose uptake and oxidation (6,7,8). In the muscles of SIRT3KOmice fed a high-fat diet, the amount of HKII bound to VDAC was reduced in association with lower enzyme activity and reduced glucose uptake as compared with wildtype control mice. This impingement on intramuscular glucose phosphorylation was accompanied by a shift in mitochondrial fuel selection, such that glucose oxidation diminished while reliance on fatty acids increased (Fig. 1), which together led to a decay in glucose tolerance. The findings by Lantier et al. (5) add to the growing complexity of how SIRT3 regulates metabolism. Previously, Hirschey et al. (9) showed that in the livers of SIRT3KO mice, hyperacetylation of long-chain acyl-CoA dehydrogenase in the fatty acid oxidation pathway led to reduced long-chain acyl-CoA dehydrogenase activity