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 #
5R01DK084171-03
Application #
8288235
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
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$340,144
Indirect Cost
$132,739
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Lee, Jieun; Choi, Joseph; Wong, G William et al. (2016) Neurometabolic roles of ApoE and Ldl-R in mouse brain. J Bioenerg Biomembr 48:13-21
Wolf, Risa M; Lei, Xia; Yang, Zhi-Chun et al. (2016) CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice. Am J Physiol Endocrinol Metab 310:E332-45
Wong, G William (2016) Renal glucose transporters 'sweeten' the pot. Exp Physiol 101:693-4
Li, Zhu; Frey, Julie L; Wong, G William et al. (2016) Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts. Endocrinology 157:4094-4103
Rodriguez, Susana; Lei, Xia; Petersen, Pia S et al. (2016) Loss of CTRP1 disrupts glucose and lipid homeostasis. Am J Physiol Endocrinol Metab 311:E678-E697
Lei, Xia; Rodriguez, Susana; Petersen, Pia S et al. (2016) Loss of CTRP5 improves insulin action and hepatic steatosis. Am J Physiol Endocrinol Metab 310:E1036-52
Tan, Stefanie Y; Little, Hannah C; Lei, Xia et al. (2016) Partial deficiency of CTRP12 alters hepatic lipid metabolism. Physiol Genomics :physiolgenomics.00111.2016
Lopez, Pablo H H; Aja, Susan; Aoki, Kazuhiro et al. (2016) Mice lacking sialyltransferase ST3Gal-II develop late onset obesity and insulin resistance. Glycobiology :
Petersen, Pia S; Wolf, Risa M; Lei, Xia et al. (2016) Immunomodulatory roles of CTRP3 in endotoxemia and metabolic stress. Physiol Rep 4:
Wolf, Risa M; Steele, Kimberley E; Peterson, Leigh A et al. (2016) C1q/TNF-Related Protein-9 (CTRP9) Levels Are Associated With Obesity and Decrease Following Weight Loss Surgery. J Clin Endocrinol Metab 101:2211-7

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