An example of the close integration of metabolism and epigenetics is CR, in which food intake is reduced by 30 to 50 percent. CR decreases NADH/NAD+ ratio and increases the AMP/ATP ratio. These changes are sensed by SIRT1 (which has HDAC activity) and AMP-activated protein kinase (AMPK), respectively. One of SIRT1’s functions is to deacetylate and activate two proteins called forkhead box protein O1 (FOXO1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a key regulator of energy metabolism. Both of these result in gene expression favoring the synthesis of glucose in the body (i.e., gluconeogenesis) (Vaquero and Reinberg 2009). AMPK directly phosphorylates PGC-1α, which enables SIRT1 to deacetylate and activate PGC-1α (Cantó and Auwerx 2011).
