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 …