AMPK, Insulin and Leptin Signaling
In general, AMPK stimulates catabolism (glycolysis, fatty acid oxidation and mitochondrial biogenesis) while inhibiting anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis) and has a direct effect on the hypothalamus to regulate appetite. Other important activities include the regulation of insulin synthesis and secretion in pancreatic islet beta-cells. AMPK activation is believed to upregulate insulin receptor substrate-1 through inhibition of the mTOR pathway, which has been implicated in the pathogenesis of insulin resistance and many types of cancer. Insulin has been shown to inhibit AMPK's hypothalamic activity. Insulin can also inhibit AMPK in fat by activating the Akt complex leading to phosphorylation of alpha-AMPK at S485/491 which causes a reduction of phosphorylation at T172 (required for AMPK activation). Furthermore, AMPK and insulin differ with respect to anabolic and catabolic processes. While AMPK inhibits anabolic processes, insulin promotes glycogen, lipid and protein synthesis. Leptin also regulates AMPK. One of leptin's many metabolic roles includes the upregulation of fatty acid oxidation in skeletal muscle via the AMPK pathway. Recent studies indicate that abnormalities in cellular lipid metabolism are involved in the pathogenesis of the metabolic syndrome, possibly because of dysregulation of AMPK and malonyl-CoA, a closely related molecule. Leptin and insulin also modulate one another. Although there is some controversy on mechanism, it appears that leptin inhibits insulin secretion from pancreatic beta-cells, either indirectly or directly. In addition, recent studies suggest that leptin down-regulates insulin by mediating the phosphorylation of IRS-1 through a JAK2, IRS-2 and PKCd dependent pathway. This serine site is known to reduce the coupling of IRS-1 to the insulin receptor. In contrast, insulin is a potent stimulator of leptin secretion from white adipocytes.