Among the secreted proteins involved in energy homeostasis, Acrp30/adiponectin, discovered in Dr. Lodish's laboratory, stands out as an important mediator of insulin sensitivity. Circulating levels of Acrp30 are correlated with metabolic dysfunctions, such as obesity and insulin resistance. Infusion of Acrp30 proteins in rodent models of insulin resistance corrected the metabolic dysfunction by increasing insulin sensitivity. While working in Dr. Lodish's laboratory in the past year, I have identified seven novel secreted Acrp30-1ike proteins that share similar modular organization as Acrp30. These proteins are designated as CTRP1 to 7 (C1q/TNF-alpha Related Protein). I have shown that CTRP2 is the closest paralog of Acrp30 and is functionally similar to Acrp30 in that both induce glycogen accumulation in muscle cells. I have also shown that CTRP2 and CTRP7 proteins form heterooligomers. My primary focus in the next three years is to characterize the metabolic functions of CTRP2 and CTRP7. I will produce recombinant CTRP2 and CTRP7 proteins individually or as heterooligomers for their biochemical and functional studies. I will investigate if CTRP2 and CTRP7 possess similar ability as Acrp30 in regulating fatty acid and glucose metabolism in cultured cells and systemically in mice. Because different oligomeric states of Acrp30 activate NF-kappaB or induce phosphorylation of AMP-activated kinase and acetyl CoA carboxylase, I will examine if similar signaling pathways are also activated by CTRP2 and CTRP7. I have shown that CTRP2 binds to its receptor in a selective and saturable manner and that this binding can be competed only by untagged CTRP2. Thus, I will employ various expression cloning strategies to elucidate the molecular identity of CTRP2 receptor. Greater understanding of the metabolic control networks orchestrated by Acrp30 and its functional paralogs will provide new avenues for pharmacologic intervention in metabolic diseases such as diabetes and obesity.
