The study investigates the role of SIRT1 in regulating mitochondrial fatty acid oxidation through the deacetylation of PGC-1α. Fasting induces PGC-1α deacetylation in skeletal muscle, and SIRT1 is essential for this process. SIRT1 deacetylates PGC-1α, which activates genes involved in mitochondrial fatty acid oxidation. Expression of the acetyltransferase GCN5 or the SIRT1 inhibitor nicotinamide reduces PGC-1α acetylation and decreases the expression of target genes in myotubes. SIRT1 is also required for the induction and maintenance of fatty acid oxidation in response to low glucose concentrations. These findings suggest that SIRT1 is a key regulator of PGC-1α, controlling the metabolic gene transcription program for mitochondrial fatty acid oxidation. This mechanism may have implications for understanding nutrient adaptation, lifespan, and metabolic diseases such as obesity and diabetes.The study investigates the role of SIRT1 in regulating mitochondrial fatty acid oxidation through the deacetylation of PGC-1α. Fasting induces PGC-1α deacetylation in skeletal muscle, and SIRT1 is essential for this process. SIRT1 deacetylates PGC-1α, which activates genes involved in mitochondrial fatty acid oxidation. Expression of the acetyltransferase GCN5 or the SIRT1 inhibitor nicotinamide reduces PGC-1α acetylation and decreases the expression of target genes in myotubes. SIRT1 is also required for the induction and maintenance of fatty acid oxidation in response to low glucose concentrations. These findings suggest that SIRT1 is a key regulator of PGC-1α, controlling the metabolic gene transcription program for mitochondrial fatty acid oxidation. This mechanism may have implications for understanding nutrient adaptation, lifespan, and metabolic diseases such as obesity and diabetes.