AMP-activated protein kinase (AMPK) regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. AMPK activation enhances SIRT1 activity by increasing cellular NAD+ levels, leading to the deacetylation and modulation of downstream targets such as PGC-1α and FOXO transcription factors. This study demonstrates that AMPK controls the expression of genes involved in energy metabolism in skeletal muscle by coordinating with SIRT1. AMPK-induced SIRT1-mediated deacetylation of PGC-1α explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism. The interplay between AMPK and SIRT1 provides a finely tuned mechanism for energy homeostasis under low nutrient availability.AMP-activated protein kinase (AMPK) regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. AMPK activation enhances SIRT1 activity by increasing cellular NAD+ levels, leading to the deacetylation and modulation of downstream targets such as PGC-1α and FOXO transcription factors. This study demonstrates that AMPK controls the expression of genes involved in energy metabolism in skeletal muscle by coordinating with SIRT1. AMPK-induced SIRT1-mediated deacetylation of PGC-1α explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism. The interplay between AMPK and SIRT1 provides a finely tuned mechanism for energy homeostasis under low nutrient availability.