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 adiponectin 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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Karki, Shakun; Ngo, Doan T M; Farb, Melissa G et al. (2017) WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans. Am J Physiol Heart Circ Physiol 313:H200-H206
Widlansky, Michael E; Puppala, Venkata K; Suboc, Tisha M et al. (2017) Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy. Vasc Med 22:189-196
Farb, Melissa G; Park, Song-Young; Karki, Shakun et al. (2017) Assessment of Human Adipose Tissue Microvascular Function Using Videomicroscopy. J Vis Exp :
Brant, Luisa C C; Wang, Na; Ojeda, Francisco M et al. (2017) Relations of Metabolically Healthy and Unhealthy Obesity to Digital Vascular Function in Three Community-Based Cohorts: A Meta-Analysis. J Am Heart Assoc 6:
Cooper, Leroy L; Palmisano, Joseph N; Benjamin, Emelia J et al. (2016) Microvascular Function Contributes to the Relation Between Aortic Stiffness and Cardiovascular Events: The Framingham Heart Study. Circ Cardiovasc Imaging 9:
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
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; 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
Lee, Richard T; Walsh, Kenneth (2016) The Future of Cardiovascular Regenerative Medicine. Circulation 133:2618-25

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