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)
Type
Research Project (R01)
Project #
5R01DK084171-05
Application #
8688752
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Seldin, Marcus M; Byerly, Mardi S; Petersen, Pia S et al. (2014) Seasonal oscillation of liver-derived hibernation protein complex in the central nervous system of non-hibernating mammals. J Exp Biol 217:2667-79
Bedont, Joseph L; LeGates, Tara A; Slat, Emily A et al. (2014) Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus. Cell Rep 7:609-22
Peterson, Jonathan M; Seldin, Marcus M; Tan, Stefanie Y et al. (2014) CTRP2 overexpression improves insulin and lipid tolerance in diet-induced obese mice. PLoS One 9:e88535
Byerly, Mardi S; Petersen, Pia S; Ramamurthy, Santosh et al. (2014) C1q/TNF-related protein 4 (CTRP4) is a unique secreted protein with two tandem C1q domains that functions in the hypothalamus to modulate food intake and body weight. J Biol Chem 289:4055-69
Wei, Zhikui; Lei, Xia; Petersen, Pia S et al. (2014) Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. Am J Physiol Endocrinol Metab 306:E779-90
Byerly, Mardi S; Swanson, Roy; Wei, Zhikui et al. (2013) A central role for C1q/TNF-related protein 13 (CTRP13) in modulating food intake and body weight. PLoS One 8:e62862
Byerly, Mardi S; Swanson, Roy D; Semsarzadeh, Nina N et al. (2013) Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite. Am J Physiol Regul Integr Comp Physiol 304:R1085-95
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
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
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 ýý and attenuates neuropeptide Y gene expression. Eur J Neurosci 37:1033-47

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