Obesity and its associated type II diabetes have become a huge medical burden in the United States, resulting in billions of dollars being spent yearly to treat these metabolic disorders. Much research is needed to understand the underlying cause of obesity-linked insulin resistance and diabetes in order to effectively treat these disorders. Acrp30/Adiponectin is an insulin-sensitizing, multimeric protein produced by adipose tissue that plays a major role in regulating whole body glucose and lipid metabolism. Allelic polymorphism and reduced serum adiponectin levels are tightly linked to diabetes and metabolic syndrome. Our laboratory has recently discovered a family of ten novel secreted proteins homologous to adiponectin, designated as Clq/TNF-related proteins 1-10 (CTRP1-10). We have shown that some members of this family, CTRP1 and CTRP9, are able to reduce blood glucose levels in vivo and activate AMPK and Akt signaling pathways in culture myotubes. Since I joined Dr. Wong's laboratory, my research focuses on characterizing the function and regulation of CTRP3 using molecular, biochemical, and in vivo approaches. In the course of my study, I identified two specific isoforms of CTRP3 (CTRP3A and CTRP3B) that resulted from alternative splicing of the gene. When expressed concurrently, CTRP3A and CTRP3B form heterotrimers and heterooligomers;this physical complex markedly prevents CTRP3B from proteolytic cleavage. I showed that leptin and inflammatory cytokines modulate the transcript and protein levels of CTRP3.1 demonstrated that the circulating levels of CTRP3 protein are higher in female mice and its levels are also significantly higher in obese (ob/ob) mice compared to lean controls. Using purified recombinant protein, I showed that CTRP3 potentiates the action of insulin in activating the Akt signaling pathway in mouse myoblasts, and furthermore injection of recombinant CTRP3 into mice significantly lowered their blood glucose levels. These results along with the structural homology of CTRP3 to adiponectin suggest important metabolic function for CTRP3. The overall goal of this proposal is to detemnine the metabolic function and mechanisms of action of CTRP3. Our overall hypothesis is that CTRP3 increases insulin sensitivity and thus enhances glucose metabolism and promote skeletal muscle proliferation. I will use both in vitro (cell culture-based) and in vivo (transgenic over-expression and recombinant protein injection) approaches to investigate the metabolic function of CTRP3. It is anticipated that this study will advance our knowledge on how adipose tissuesecreted factors (collectively termed adipokine) coordinate systemic energy balance and thus provide novel insights to treat metabolic disorders.
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