Metabolic homeostasis is inherently ?systems physiology?. Cell-autonomous processes within each tissue and organ must be tightly coordinated to allow for the integrative control of whole-body metabolism. This integration is achieved in part by the vagal nerve system, connecting the brain to visceral organs. Tissue crosstalk in the periphery is instead largely mediated by secreted hormones. Disruption of hormonal circuits underlying these peripheral organ communications is causally linked to metabolic disorders. Yet, we lack fundamental knowledge about mechanisms underlying this hormonal regulation in both physiologic and pathologic conditions. Toward this end, our efforts to map the organ-level metabolic circuits have largely centered on understanding the function and mechanisms of action of a family of highly conserved secreted hormones?C1q/TNF-related proteins (CTRP1-15)?that we initially described. In the last decade, we have generated numerous enabling tools and mouse models that have promoted major advances in understanding CTRP biology and the critical roles they play in sugar and fat metabolism, including in disease contexts. In this competitive renewal application, we propose focused studies of CTRP2, a poorly characterized CTRP family member that is enriched in adipose tissue. Using novel mouse models, we discovered that CTRP2 is required for maintaining systemic lipid homeostasis. Our preliminary data suggest that CTRP2 is a novel anti-lipolytic hormone within the fat tissue, as well as an important regulator of hepatic triglyceride, cholesterol, and phospholipid metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP2 regulates lipid metabolism in adipose tissue (Aim 1) and liver (Aim 2), its major target tissues. The completion of this project will provide critical insights into the metabolic gene circuits and signaling networks directly regulated by CTRP2 in adipocytes and hepatocytes to control local and systemic lipid metabolism. Our studies have the potential to provide fundamental insights that ultimately inform innovative strategies to 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 CTRP2, a novel hormone produces in fat tissue and circulates in blood, regulates glucose and lipid metabolism will provide new avenues to treat obesity and type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
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
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 58 publications