Obesity has emerged as one of the most critical health care problems in the US as 69% of the US population is currently overweight or obese. Adipose tissue dysfunction is an essential hallmark linking obesity to the pathogenesis of cardiometabolic disease, and prior work form our group has demonstrated that qualitative properties of adipose tissue shape systemic phenotypes. In particular, impaired adipose tissue angiogenesis in obesity has been associated with inflammation and metabolic dysfunction; however pathogenic mechanisms are incompletely understood. We describe a novel endogenous isoform of vascular endothelial growth factor (VEGF-A), VEGF-A165b that is selectively over-expressed in obesity and inhibits angiogenesis. Our preliminary data suggest that perturbations in the Wnt5a signaling system up-regulates VEGF-A165b under conditions of obesity that is modified by bariatric surgical weight loss.
In aim 1, we will examine adipose depot-specific microvascular angiogenic responses in biopsied fat samples from 150 obese and 50 lean subjects. We will characterize VEGF-A isoforms in relation to angiogenic capacity and vascularization. We hypothesize that inhibitory isoform VEGF-A165b will be up- regulated in obesity, associated with anti-angiogenic actions in fat, and relate to whole body metabolic dysfunction.
In aim 2, specific inhibitors of Wnt signaling will be employed using human adipose tissue samples secured from aim 1 to provide a molecular framework for understanding the regulation of VEGF-A 165b expression.
In aim 3, we will re-examine adipose angiogenic capacity and VEGF isoform expression at 6 months following bariatric surgery in the same 150 obese subjects from aim 1. We will test whether relevant molecular pathways specifically identified in aim 2 are influenced by weight reduction. We seek to identify novel determinants of adipose tissue biology and angiogenesis in relation to metabolic changes which will develop in association with marked weight loss in obese individuals. Our proposal may identify the Wnt5a-VEGF-A 165b axis as a novel modulator of angiogenesis, adipose tissue biology, and consequently, systemic disease in clinical obesity and potentially lead to the identification of new therapeutic targets.

Public Health Relevance

The number of obese Americans persists at record levels as 69% of the US population is currently overweight or obese. Cardiovascular disease is the main cause of death in this population and this project seeks to investigate clinically important mechanisms of obesity-related vascular and metabolic disease as an area of high priority research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126141-03
Application #
9172995
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Mcdonald, Cheryl
Project Start
2014-11-14
Project End
2019-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Farb, Melissa G; Park, Song-Young; Karki, Shakun et al. (2017) Assessment of Human Adipose Tissue Microvascular Function Using Videomicroscopy. J Vis Exp :
Zuriaga, María A; Fuster, José J; Farb, Melissa G et al. (2017) Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation. Sci Rep 7:17326
MacLauchlan, Susan; Zuriaga, Maria A; Fuster, José J et al. (2017) Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. Arthritis Res Ther 19:166
Fuster, José J; MacLauchlan, Susan; Zuriaga, María A et al. (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842-847
Zuriaga, Maria A; Fuster, Jose J; Gokce, Noyan et al. (2017) Humans and Mice Display Opposing Patterns of ""Browning"" Gene Expression in Visceral and Subcutaneous White Adipose Tissue Depots. Front Cardiovasc Med 4:27
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
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
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
Farb, Melissa G; Karki, Shakun; Park, Song-Young et al. (2016) WNT5A-JNK regulation of vascular insulin resistance in human obesity. Vasc Med 21:489-496
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

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