It is becoming increasingly appreciated that adipose tissue macrophage activation plays an important role in the development of chronic inflammation and metabolic dysfunction associated with obesity. Obese organisms also display capillary rarefaction and diminished perfusion in their fat pads. Adipose tissue hypoxia is thought to be linked to inflammation because this stress will favor adipocyte necrosis and lead to macrophage recruitment. In turn, the fat pad milieu of an obese organism will favor macrophage activation and lead to further degradation of the vascular bed. Thus, it is reasonable to speculate that obesity favors a vicious cycle of hypoxia and inflammation in adipose tissue. Adiponectin is a fat-derived cytokine that has both anti-inflammatory and pro-angiogenic activities. Adipose tissues from lean organisms express high levels of adiponectin and there is a progressive decline in adiponectin expression as fat mass increases. Both infiammatory cytokines and hypoxia will lead to reductions in adiponectin expression by adipocytes. Published work from my lab has shown that adiponectin will promote endothelial cell function and angiogenesis in a variety of ischemia models, but the role of adiponecfin in fat pad vascularization has never been examined. Furthermore, while adiponectin has recognized anti-inflammatory properties, its effect on adipose tissue macrophage polarization has never been systematically delineated. In this proposal, we will perform a series of experiments to investigate the role of adiponectin in fat pad biology to define the functional interrelationship between inflammation and hypoxia in obesity. The proposed experiments will test the hypotheses that adiponectin functions as a direct regulator of macrophage phenotype, favoring anti-inflammatory, M2-like polarization, and that it promotes fat pad perfusion. We propose that these activities of adiponectin control the microenvironment of the fat pad, and thereby infiuence systemic metabolism and cardiovascular function. Furthermore, gene ablation experiments in vitro and in mouse genetic models will be performed to determine the identifies of the receptors that confer adiponectin?s actions on fat pad perfusion and inflammation.

Public Health Relevance

Clinical studies have documented that obese individuals differ markedly in their abilifies to cope with excess fat tissue or develop a chronic low-grade inflammatory state and insulin resistance. This research will examine how the microenvironment of the fat pad, determined by the status of the vascular bed and composition of inflammatory cells, influences the overall metabolic health of the organism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL081587-08
Application #
8438331
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$508,062
Indirect Cost
$197,701
Name
Boston University
Department
Type
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Maruyama, Sonomi; Nakamura, Kazuto; Papanicolaou, Kyriakos N et al. (2016) Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med 8:949-66
Nakamura, Kazuto; Sano, Soichi; Fuster, José J et al. (2016) Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury. J Biol Chem 291:2566-75
Fetterman, Jessica L; Holbrook, Monica; Flint, Nir et al. (2016) Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling. Atherosclerosis 247:207-17
Krzywanski, David M; Moellering, Douglas R; Westbrook, David G et al. (2016) Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry. Circ Cardiovasc Genet 9:26-36
Tampakakis, Emmanouil; Tabit, Corey E; Holbrook, Monika et al. (2016) Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults. J Am Heart Assoc 5:
Fetterman, Jessica L; Holbrook, Monica; Westbrook, David G et al. (2016) Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease. Cardiovasc Diabetol 15:53
Bretón-Romero, Rosa; Feng, Bihua; Holbrook, Monika et al. (2016) Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling. Arterioscler Thromb Vasc Biol 36:561-9
Lee, Richard T; Walsh, Kenneth (2016) The Future of Cardiovascular Regenerative Medicine. Circulation 133:2618-25
Fuster, José J; Ouchi, Noriyuki; Gokce, Noyan et al. (2016) Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease. Circ Res 118:1786-807
Mohandas, Appesh; Suboc, Tisha B; Wang, Jingli et al. (2015) Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension. Vasc Med 20:401-8

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