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.

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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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Boston University
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Fuster, José J; Zuriaga, María A; Ngo, Doan Thi-Minh et al. (2015) Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64:1235-48
Romero, Freddy; Shah, Dilip; Duong, Michelle et al. (2015) A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis. Am J Respir Cell Mol Biol 53:74-86
Kikuchi, Ryosuke; Nakamura, Kazuto; MacLauchlan, Susan et al. (2014) An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med 20:1464-71
Ngo, Doan T M; Farb, Melissa G; Kikuchi, Ryosuke et al. (2014) Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation 130:1072-80
Tan, Peng H; Tyrrell, Helen E J; Gao, Liquan et al. (2014) Adiponectin receptor signaling on dendritic cells blunts antitumor immunity. Cancer Res 74:5711-22
Hartman, Mor-Li; Shirihai, Orian S; Holbrook, Monika et al. (2014) Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus. Vasc Med 19:67-74
Nakamura, Kazuto; Fuster, José J; Walsh, Kenneth (2014) Adipokines: a link between obesity and cardiovascular disease. J Cardiol 63:250-9
Shimizu, Ippei; Aprahamian, Tamar; Kikuchi, Ryosuke et al. (2014) Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 124:2099-112
Yoshida, Sumiko; Fuster, José Javier; Walsh, Kenneth (2014) Adiponectin attenuates abdominal aortic aneurysm formation in hyperlipidemic mice. Atherosclerosis 235:339-46
Parker-Duffen, Jennifer L; Walsh, Kenneth (2014) Cardiometabolic effects of adiponectin. Best Pract Res Clin Endocrinol Metab 28:81-91

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