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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK084607-03
Application #
8133552
Study Section
Special Emphasis Panel (ZDK1-GRB-W (M1))
Program Officer
Castle, Arthur
Project Start
2009-09-01
Project End
2012-01-03
Budget Start
2011-09-01
Budget End
2012-01-03
Support Year
3
Fiscal Year
2011
Total Cost
$19,365
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Byerly, Mardi S; Al Salayta, Muhannad; Swanson, Roy D et al. (2013) Estrogen-related receptor ? deletion modulates whole-body energy balance via estrogen-related receptor ? and attenuates neuropeptide Y gene expression. Eur J Neurosci 37:1033-47
Peterson, Jonathan M; Seldin, Marcus M; Wei, Zhikui et al. (2013) CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism. Am J Physiol Gastrointest Liver Physiol 305:G214-24
Wei, Zhikui; Seldin, Marcus M; Natarajan, Niranjana et al. (2013) C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis. J Biol Chem 288:10214-29
Peterson, Jonathan M; Wei, Zhikui; Seldin, Marcus M et al. (2013) CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol 305:R522-33
Seldin, Marcus M; Peterson, Jonathan M; Byerly, Mardi S et al. (2012) Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem 287:11968-80
Peterson, Jonathan M; Aja, Susan; Wei, Zhikui et al. (2012) CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition. J Biol Chem 287:1576-87
Huang, Tai-Chung; Sahasrabuddhe, Nandini A; Kim, Min-Sik et al. (2012) Regulation of lipid metabolism by Dicer revealed through SILAC mice. J Proteome Res 11:2193-205
Wei, Zhikui; Peterson, Jonathan M; Lei, Xia et al. (2012) C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes. J Biol Chem 287:10301-15
Wei, Zhikui; Peterson, Jonathan M; Wong, G William (2011) Metabolic regulation by C1q/TNF-related protein-13 (CTRP13): activation OF AMP-activated protein kinase and suppression of fatty acid-induced JNK signaling. J Biol Chem 286:15652-65
Zheng, Qijun; Yuan, Yuexing; Yi, Wei et al. (2011) C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol 31:2616-23

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