The goal of this proposal is to understand the role of and mechanism by which the novel adipokine, CTRP9, regulates whole body energy balance. Adipose tissue-secreted factors (collectively termed adipokines) play important roles in regulating systemic insulin sensitivity by controlling glucose and lipid utilization in the peripheral tissues. One widely studied adipokine is adiponectin, well-known for being an insulin-sensitizer that promotes fatty acid oxidation in muscles and suppresses gluconeogenesis in liver. However, adiponectin-null mice display variable and relatively mild metabolic dysfunctions, suggesting the existence of compensatory mechanisms. We have recently discovered a novel family of ten adiponectin paralogs, designated as C1q/TNF-related protein (CTRP)-1 to 10. CTRP9, the closest paralog of adiponectin, is expressed by adipose tissue and circulates in plasma as a multimeric glycoprotein. CTRP9 forms homo-oligomers as well as heterotrimers with adiponectin. Adenovirus-mediated over-expression of CTRP9 in obese (ob/ob) mice leads to a modest but significant decrease in blood glucose levels. Transgenic (Tg) mice with elevated circulating CTRP9 are significantly leaner due to reduced fat mass. When challenged with a high-fat diet, CTRP9 Tg mice are resistant to body weight gain, have significantly lower fasting glucose and insulin levels, better lipid profiles, and exhibit marked improvements in glucose tolerance tests. These in vivo phenotypes correlate with the ability of CTRP9 to suppress gluconeogenesis and promote fatty acid oxidation in vitro. Our data support the hypothesis that CTRP9 regulates body weight and adiposity by controlling glucose and fatty acid utilization in tissues. To understand the mechanism by which CTRP9 exerts its beneficial metabolic function, we aim to address the following questions: 1) what are the target tissues of CTRP9;2) what specific metabolic processes (e.g., glucose uptake and fatty acid oxidation) are regulated by CTRP9;3) what is the mechanism by which CTRP9 controls glucose and fatty acid utilization in vitro and in vivo;4) what metabolic signaling pathways (e.g., Akt and/or AMPK) are activated by CTRP9 in responsive cell types;5) what is the mechanism by which CTRP9 regulates body weight, adiposity, and insulin sensitivity in mice;and, 6) is there a possible therapeutic potential of CTRP9 in restoring insulin sensitivity and normalizing glucose and lipid profiles in a diet-induced obesity mouse model and a genetic model of obesity (as in leptin-deficient ob/ob mice)? Together, these studies will provide fundamental insights into how adipokines in general, and CTRP9 in particular, connect multiple tissues to coordinate systemic energy balance. These studies will likely provide new avenues for the treatment of obesity and diabetes.

Public Health Relevance

The incidence of obesity and closely-linked diseases (e.g. diabetes and cardiovascular disease) has risen dramatically in recent years. A basic understanding of the molecular, cellular, and physiological mechanisms involved in controlling whole body nutrient utilization and energy balance will provide new avenues to treat obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084171-04
Application #
8490719
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$328,239
Indirect Cost
$128,093
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Stewart, Ashley N; Tan, Stefanie Y; Clark, David J et al. (2018) N-linked glycosylation dependent and independent mechanisms regulating CTRP12 cleavage, secretion, and stability. Biochemistry :
Little, Hannah C; Tan, Stefanie Y; Cali, Francesca M et al. (2018) Multiplex Quantification Identifies Novel Exercise-regulated Myokines/Cytokines in Plasma and in Glycolytic and Oxidative Skeletal Muscle. Mol Cell Proteomics 17:1546-1563
Gupta, Rajesh; Nguyen, Dan C; Schaid, Michael D et al. (2018) Complement 1q-like-3 protein inhibits insulin secretion from pancreatic ?-cells via the cell adhesion G protein-coupled receptor BAI3. J Biol Chem 293:18086-18098
Hamoud, Noumeira; Tran, Viviane; Aimi, Takahiro et al. (2018) Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. Nat Commun 9:4470
Wolf, Risa M; Jaffe, Andrew E; Steele, Kimberley E et al. (2018) Cytokine, chemokine and cytokine receptor changes are associated with metabolic improvements after bariatric surgery. J Clin Endocrinol Metab :
Cisternas, Pedro; Zolezzi, Juan M; Martinez, Milka et al. (2018) Wnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease. J Neurochem :
Yang, Haojun; Ralle, Martina; Wolfgang, Michael J et al. (2018) Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes. PLoS Biol 16:e2006519
Cisternas, Pedro; Martinez, Milka; Ahima, Rexford S et al. (2018) Modulation of Glucose Metabolism in Hippocampal Neurons by Adiponectin and Resistin. Mol Neurobiol :
Stevens, Richard L; McNeil, H Patrick; Wensing, Lislaine A et al. (2017) Experimental Arthritis Is Dependent on Mouse Mast Cell Protease-5. J Biol Chem 292:5392-5404
Yan, Wenjun; Guo, Yongzhen; Tao, Ling et al. (2017) C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways. Circulation 136:2162-2177

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