Integrated control of metabolism requires inter-organ communication in the peripheral tissues; this crosstalk is largely orchestrated by secreted hormones. Our long-term goal is to understand hormonal control of energy homeostasis. This proposal is a competitive renewal of a continuing research project focusing on a conserved family of secreted plasma proteins we identified, the C1q/TNF-related proteins (CTRPs). In the last decade, we have provided new and important knowledge on the roles and contributions of various CTRP hormones to whole-body glucose and lipid metabolism. In the next budget cycle, we will focus our studies on CTRP6, a protein with fundamentally different modes of action compared to other CTRPs characterized to date. Our preliminary studies on CTRP6, combined with recent studies of other CTRP family members, has led to the Yin and Yang concept, in which different CTRPs function as positive or negative regulators of substrate metabolism. The central hypothesis, based on gain- and loss-of-function mouse models, is that CTRP6 functions as a negative physiological regulator of glucose metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP6 negatively regulates glucose metabolism at the tissue (Aim 1) and cellular (Aim 2) levels. We expect Aim 1 and Aim 2 to provide critical insights into metabolic gene circuits and signaling networks directly regulated by CTRP6 in adipocytes, skeletal muscle, and liver to control systemic energy metabolism. Since over-activation of the CTRP6-regulated pathways contributes to obesity-linked insulin resistance and diabetes, our studies have the potential to provide insights that lead to innovative strategies to reverse or mitigate metabolic disease outcomes in clinical settings.

Public Health Relevance

Secreted hormones play a vital role in controlling energy metabolism. A basic understanding of the mechanism by which CTRP6, a novel hormone circulates in blood, regulates glucose and lipid metabolism will provide new avenues to treat obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK084171-07S1
Application #
9538449
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2010-07-15
Project End
2019-06-30
Budget Start
2017-08-15
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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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 :
Petersen, Pia S; Lei, Xia; Wolf, Risa M et al. (2017) CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress. Am J Physiol Endocrinol Metab 312:E309-E325
Lei, Xia; Seldin, Marcus M; Little, Hannah C et al. (2017) C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance. J Biol Chem 292:14836-14850

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