Organisms must be able to selectively tailor their ability to use the macronutrients of carbohydrate, protein, and fat based on their availability. In different cell types, how the nutrient fluctuations are sensed and the mechanisms by which the pathways of central metabolism are switched to favor the use of one particular nutrient type over another are topics of intense interest. Protein acetylation is one major evolutionary conserved mechanism by which nutrient fluctuations are sensed within cells and subsequently coupled with metabolic switching. In this review, we present the case of PGC-1α acetylation and how the control of PGC-1α's activity by acetylation sets into motion a wide range of metabolic adaptations that makes this protein an exemplary model for acetylation-mediated mechanisms of nutrient sensing and communication.