Principal Investigator Harvey Lodish
Several years ago we cloned Adiponectin, a novel protein hormone that is secreted by adipocytes and linked physiologically and genetically to development of Type II (adult-onset) diabetes. We are cloning and characterizing the adiponectin receptors and investigating the signaling pathways that induce fat and glucose catabolism by muscle, enhance glycogen accumulation in muscle, and inhibit gluconeogenesis in liver. Another aspect focuses on the signal transduction pathways for TNF-a, an autocrine factor produced by adipocytes and that induces insulin resistance, in part, by down-regulating Adiponectin and other adipocyte proteins involved in fat and glucose metabolism.
Adiponectin has four domains: a cleaved amino-terminal signal sequence, a region without homology to known proteins, a collagen-like region, and a globular segment at the carboxy-terminus. The three-dimensional structure of the globular domain is strikingly similar to that of TNF-alpha even though there is no homology at the primary sequence level. Like TNF-alpha the globular domain forms homotrimers, and intermolecular disulfide bonds generate hexameric and high molecular weight Adiponectin species.
In collaboration with the Ruderman laboratory at B. U. Medical School, Tsu-Shuen Tsao showed that treatment of rat striated muscle with trimeric adiponectin led to phosphorylation and activation of AMP-activated protein kinase (AMPK), an enzyme that when activated causes increases in muscle fatty acid oxidation, glucose uptake and oxidation, and insulin sensitivity. Adiponectin- mediated activation of AMPK caused phosphorylation and thus diminished activity of acetyl CoA carboxylase, a corresponding decrease in the concentration of malonyl CoA, and a corresponding increase in long- chain fatty acid oxidation. In addition, adiponectin caused an increase in glucose uptake. Both in vivo and in muscle culture adiponectin most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC, via activation of AMPK and perhaps other signal transduction proteins.