Yamauchi et al. show how AMPK is activated by the hormone adiponectin, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
In recent years it has emerged that adipose tissue is much more important than previously thought, operating as an endocrine organ and releasing hormones in response to specific extracellular stimuli or changes in metabolic status. These secreted proteins are known as adipokines, and include leptin, TNF adipsin and adiponectin (Ad). It has previously been reported that Ad decreases insulin resistance by increasing fatty-acid oxidation, which reduces the triglyceride content in tissues of obese and type II diabetic mice. Ad also reportedly suppresses hepatic glucose production, but although it clearly has an important role to play, the signaling pathways that mediate adiponectin-dependent effects remain undefined.
Now, Yamauchi et al. have taken steps towards elucidating this pathway. They show that Ad stimulates the phosphorylation and activation of 5'-AMP-activated protein kinase (AMPK) in skeletal muscle, and in the liver in vivo. Ad also stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC) in cultured myocytes, leading to fatty-acid oxidation, glucose uptake and lactate production. Phosphorylation of ACC in the liver leads to a reduction of enzymes involved in gluconeogenesis, and in vivo to a reduction in glucose levels. Blocking AMPK activation with a catalytically inactive 2AMPK mutant, which acts as a dominant negative on both and AMPK activities in skeletal muscle, antagonizes Ad signaling. This leads to reductions in ACC phosphorylation, fatty-acid oxidation, glucose uptake and lactate production in C2C12 myocytes. Furthermore, activation of AMPK proved necessary for the Ad-induced stimulation of ACC phosphorylation in isolated primary hepatocytes. Thus, the authors propose that AMPK action in the liver is necessary for Ad to reduce levels of the enzymes involved in gluconeogenesis, and trigger an in vivo reduction in glucose levels.
These results demonstrate the potential of the AMPK pathway as a future target for therapeutic agents intended to reduce lipotoxicity in patients with obesity and type II diabetes.
The Signaling Gateway Team
References
Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.
Nature Medicine, 8, 1288–1295 (November 2002); 10.1038/nm788 | PubMed |
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