Omentin Activates AMP-activated Protein Kinase and Plays a Role in Energy Metabolism and Immune Response

Abstract

Obesity is a risk factor for type 2 diabetes, cardiovascular diseases, and other diseases as well. It has been recognized that adipose tissue is an active endocrine organ that secrets many adipokines to regulate energy metabolism and inflammation. Our group has identified omentin as among the first omental fat-specific adipokine in humans and has shown that omentin can enhance insulin-mediated glucose transport and AKT phosphorylation in adipocytes. Here, I have further characterized the role of omentin in metabolism and inflammation. In this study, I first expressed omentin protein in High-Five insect cell expression system and then purified it with a galactose-conjugated affinity column. In C2C12 myocytes, omentin increases AMP-activated protein kinase (AMPK) phosphorylation, which is known to be important for energy metabolism. Downstream target of AMPK, acetyl-CoA carboxylase (ACC), is also phosphorylated in a dose-dependent manner. Accordingly, fatty acid oxidation was increased with omentin treatment dose-dependently. Omentin inhibits phosphorylation of another downstream target of AMPK, p70S6K, and increases insulin-mediated glucose uptake, indicating that omentin may enhance insulin activity by this mechanism. Moreover, administration of omentin in mice increases ACC phosphorylation in muscle and liver, and improves glucose disposal in an intra-peritoneal glucose tolerance test. In endothelial cells, omentin activates AMPK and eNOS phosphorylation. I also demonstrate that omentin increases cell migration with human primary mesothelial cells and breast cancer cell line MCF-7. Finally, I show that IL-6 induces omentin secretion in endothelial cells and mesothelial cells. These findings suggest that omentin may participate in immune response. To explore possible mechanism of omentin signaling, I used yeast two hybrid system and identified a possible omentin interactive protein, Loc401397. The full length gene has not been cloned yet, probably due to the upstream GC-rich region which might jeopardize the reverse transcription. In summary, in this study I have demonstrated that omentin activates AMPK and regulates energy metabolism in vitro and in vivo. Moreover, omentin activates AMPK-eNOS pathway and promotes migration of mesothelial cells to defend host during infection. These findings suggest that omentin is a multifunctional protein that plays a role in both energy metabolism and inflammatory response.