SIRT1 and PGC-1α regulate mitochondrial fatty acid oxidation in skeletal muscle during fasting. The study shows that fasting induces PGC-1α deacetylation in skeletal muscle, with SIRT1 playing a key role in this process. SIRT1 deacetylates PGC-1α, which is necessary for the activation of genes involved in mitochondrial fatty acid oxidation. Acetyltransferase GCN5 or SIRT1 inhibitor nicotinamide induces PGC-1α acetylation, decreasing its target gene expression. SIRT1 is required for fatty acid oxidation in response to low glucose concentrations. SIRT1 deacetylates PGC-1α in skeletal muscle cells, and this process is essential for the expression of genes involved in mitochondrial fatty acid oxidation. SIRT1 is also localized to promoters of PGC-1α target genes, suggesting a regulatory role in their expression. SIRT1 regulates mitochondrial and fatty acid metabolism by modulating PGC-1α activity. GCN5 and nicotinamide regulate mitochondrial and fatty acid metabolism in skeletal muscle cells by affecting PGC-1α acetylation. SIRT1 is required to switch on fatty acid oxidation in response to low glucose concentrations. SIRT1 is a key regulator of PGC-1α, which controls the expression of genes involved in mitochondrial fatty acid oxidation. The study highlights the importance of SIRT1 in nutrient deprivation conditions, as it allows cells to switch from glucose to fatty acid oxidation. SIRT1 is essential for the metabolic adaptation that enables cells to survive periods of low nutrients and integrate muscle cells into the physiological response of food deprivation to spare glucose for neuronal and red blood cells. The findings have implications for understanding selective nutrient adaptation and its impact on lifespan or metabolic diseases such as obesity and diabetes.SIRT1 and PGC-1α regulate mitochondrial fatty acid oxidation in skeletal muscle during fasting. The study shows that fasting induces PGC-1α deacetylation in skeletal muscle, with SIRT1 playing a key role in this process. SIRT1 deacetylates PGC-1α, which is necessary for the activation of genes involved in mitochondrial fatty acid oxidation. Acetyltransferase GCN5 or SIRT1 inhibitor nicotinamide induces PGC-1α acetylation, decreasing its target gene expression. SIRT1 is required for fatty acid oxidation in response to low glucose concentrations. SIRT1 deacetylates PGC-1α in skeletal muscle cells, and this process is essential for the expression of genes involved in mitochondrial fatty acid oxidation. SIRT1 is also localized to promoters of PGC-1α target genes, suggesting a regulatory role in their expression. SIRT1 regulates mitochondrial and fatty acid metabolism by modulating PGC-1α activity. GCN5 and nicotinamide regulate mitochondrial and fatty acid metabolism in skeletal muscle cells by affecting PGC-1α acetylation. SIRT1 is required to switch on fatty acid oxidation in response to low glucose concentrations. SIRT1 is a key regulator of PGC-1α, which controls the expression of genes involved in mitochondrial fatty acid oxidation. The study highlights the importance of SIRT1 in nutrient deprivation conditions, as it allows cells to switch from glucose to fatty acid oxidation. SIRT1 is essential for the metabolic adaptation that enables cells to survive periods of low nutrients and integrate muscle cells into the physiological response of food deprivation to spare glucose for neuronal and red blood cells. The findings have implications for understanding selective nutrient adaptation and its impact on lifespan or metabolic diseases such as obesity and diabetes.