Adiponectin Acts through AMPK

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Adiponectin is a peptide hormone (224 amino acids) produced almost exclusively in adipose tissue. It circulates in the blood and powerfully affects the metabolism of fatty acids and carbohydrates in liver and muscle. Adiponectin increases the uptake of fatty acids from the blood by myocytes and the rate at which fatty acids undergo 3 oxidation in the muscle. It also blocks fatty acid synthesis and gluconeogenesis in hepatocytes, and it stimulates glucose uptake and catabolism in muscle and liver (Fig. 23-36). These effects of adiponectin occur indirectly, through activation of the key regulatory enzyme AMPK by increased cytosolic [AMP]. Increased [AMP] also results from ATP consumption during intense muscular activity, but it can be brought about by adiponectin through other, unknown mechanisms. When activated, AMPK phosphorylates a number of target proteins critical to the metabolism of fatty acids and carbohydrates, with profound effects on the metabolism of the whole animal.

One enzyme regulated by AMPK is acetyl-CoA car-boxylase, which produces malonyl-CoA, the first intermediate committed to fatty acid synthesis. Malonyl-CoA is a powerful inhibitor of the enzyme carnitine acyl-transferase I, which starts the process of 3 oxidation by transporting fatty acids into the mitochondrion (see Fig. 17-6). By phosphorylating and inactivating acetyl-CoA carboxylase, AMPK inhibits fatty acid synthesis while relieving the inhibition (by malonyl-CoA) of 3 oxidation (Fig. 23-37).

Mice with defective adiponectin genes are less sensitive to insulin than those with normal adiponectin, and they show poor glucose tolerance; ingestion of dietary carbohydrate causes a long-lasting rise in their blood glucose. These metabolic defects resemble those of

Adiponectin

t Fatty acid uptake t Glycolysis tb Oxidation 4- Gluconeogenesis t Fatty acid uptake t Glycolysis tb Oxidation 4- Gluconeogenesis t Glucose uptake 4-Fatty acid synthesis

FIGURE 23-36 Effects of adiponectin on muscle and adipose tissue.

By interacting with its receptors on the surface of myocytes and hepatocytes, adiponectin activates their AMPK. The activated kinase phosphorylates key metabolic enzymes (see Fig. 23-3 7, for example), shifting metabolism toward oxidation of fatty acids and away from lipid and glucose synthesis.

FIGURE 23-37 Regulation of fatty acid synthesis and ß oxidation by AMPK action on acetyl-CoA carboxylase. When activated by elevated 5'-AMP, AMPK phosphorylates a Thr residue on acetyl-CoA carboxylase (ACC), inactivating it. This prevents the synthesis of malonyl-CoA, the first intermediate in fatty acid synthesis, and reduction in [malonyl-CoA] relieves the inhibition of carnitine acyl-transferase I, allowing fatty acids to enter the mitochondrial matrix to undergo ß oxidation.

FIGURE 23-37 Regulation of fatty acid synthesis and ß oxidation by AMPK action on acetyl-CoA carboxylase. When activated by elevated 5'-AMP, AMPK phosphorylates a Thr residue on acetyl-CoA carboxylase (ACC), inactivating it. This prevents the synthesis of malonyl-CoA, the first intermediate in fatty acid synthesis, and reduction in [malonyl-CoA] relieves the inhibition of carnitine acyl-transferase I, allowing fatty acids to enter the mitochondrial matrix to undergo ß oxidation.

Carnitine Acyltransferase Activity

humans with type II diabetes, who also are insulin-insensitive and clear glucose from the blood only slowly. Indeed, individuals with obesity or type II diabetes have lower blood adiponectin levels than nondia-betic controls. Moreover, the drugs used in treatment of type II diabetes—the thiazolidinediones, such as rosigli-tazone (Avandia) and pioglitazone (Actos) (p. 807)— increase the expression of adiponectin mRNA in adipose tissue and increase blood adiponectin levels in experimental animals; they also activate AMPK. It appears that adiponectin, acting through AMPK, modulates the sensitivity of cells and tissues to insulin. Perhaps this hormone will prove to be one of the links between type II diabetes and its most important predisposing factor, obesity.

Three factors improve the health of individuals with type II diabetes: regular exercise, use of thiazolidinediones, and dietary restriction. We have seen that exercise activates AMPK, as does adiponectin, and that thiazolidinediones increase the concentration of adiponectin in plasma, increasing insulin sensitivity. Dietary restriction may act by regulating the expression of genes that encode proteins involved in fatty acid oxidation and in energy expenditure via thermogenesis.

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