Energy homeostasis in mammals is achieved through tight regulation of tissue-specific metabolic pathways that become dysregulated in metabolic diseases including diabetes and obesity. At the molecular level, main nutrient and hormonal signaling pathways impinge on expression of genes encoding for metabolic enzymes. Among the major components of this transcriptional circuitry are the PGC-1α transcriptional complexes. An important regulatory mechanism of this complex is through acetylation and SIRT1-mediated lysine de-acetylation under low nutrient conditions. Activation of SIRT1 can mimic several metabolic aspects of calorie restriction that target selective nutrient utilization and mitochondrial oxidative function to regulate energy balance. Thus, understanding the PGC-1α and SIRT1 pathways might have important implications for comprehending metabolic and age-associated diseases.