SIRT1 mediates metabolic benefits in various tissues. Major metabolic tissues, such as liver, heart, white adipose tissue (WAT), and skeletal muscle are depicted to illustrate SIRT1 functions. In the liver, SIRT1 supports gluconeogenesis via peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α) and forkhead box O1 (FOXO1) [57], and facilitates CREB-regulated transcription coactivator 2 (CRTC2) degradation upon prolonged fasting [56]. SIRT1 inhibits glycolysis by repressing glycolytic enzyme phosphoglycerate mutase-1 (PGAM-1) [59]. In the liver, SIRT1 responds to fasting and promotes fatty acid oxidation by activating peroxisome proliferator-activated receptor α (PPARα) [58] and inhibits fatty acid synthesis by targeting sterol regulatory element binding protein 1c (SREBP1c) for degradation [63]. SIRT1 is a positive regulator of liver X receptor (LXR) and thus regulates whole-body cholesterol homeostasis [64]. In the skeletal muscle, SIRT1 exerts similar actions on increasing fatty acid utilization, and reduces glycolysis as described above [75]. Here, SIRT1 and AMP-activated protein kinase (AMPK) comprise a reciprocal positive regulating loop. AMPK activates SIRT1 by upregulating the gene encoding the NAD+ synthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) [78, 79]. Reciprocally, SIRT1 activates AMPK by deacetylating liver kinase B1 (LKB1) [80]. In WAT, SIRT1 mobilizes fat from WAT via PPARγ to drive lipid utilization in liver and muscle [83]. In addition, by deacetylating PPARγ to facilitate PR domain containing 16 (Prdm16) binding, SIRT1 drives white fat browning to enhance energy expenditure [84]. SIRT1 protein is degraded post high-fat diet challenge by activated caspase I [29] and can be upregulated by adiponectin [82]. SIRT1 also benefits the heart by increasing ischemic tolerance via an activation of endothelial nitric oxide synthase (eNOS) [85]. SIRT1 additionally protects against cardiac hypertrophy through PPARα activation [87]. Targets that are directly activated by SIRT1 are shown in green. Those repressed or inhibited by SIRT1 are shown in pink.