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PNAS 109 (15): 5874-5879

Copyright © 2012 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / PHYSIOLOGY

Dichotomous effects of VEGF-A on adipose tissue dysfunction

Kai Suna, Ingrid Wernstedt Asterholma,1, Christine M. Kusminskia,1, Ana Carolina Buenoa,b, Zhao V. Wanga, Jeffrey W. Pollardc, Rolf A. Brekkend, and Philipp E. Scherera,e,2

aDepartment of Internal Medicine, Touchstone Diabetes Center, eDepartment of Cell Biology, and dHamon Center for Therapeutic Oncology and Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Pediatrics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil; and cDepartment of Developmental and Molecular Biology, Center of Reproductive Biology and Women's Health, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461

Edited* by Roger H. Unger, Touchstone Center for Diabetes Research, Dallas, TX, and approved February 29, 2012 (received for review January 10, 2012)

Abstract: Obese fat pads are frequently undervascularized and hypoxic, leading to increased fibrosis, inflammation, and ultimately insulin resistance. We hypothesized that VEGF-A–induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrient exchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpression model, we demonstrate that the local up-regulation of VEGF-A in adipocytes improves vascularization and causes a "browning" of white adipose tissue (AT), with massive up-regulation of UCP1 and PGC1α. This is associated with an increase in energy expenditure and resistance to high fat diet-mediated metabolic insults. Similarly, inhibition of VEGF-A–induced activation of VEGFR2 during the early phase of high fat diet-induced weight gain, causes aggravated systemic insulin resistance. However, the same VEGF-A–VEGFR2 blockade in ob/ob mice leads to a reduced body-weight gain, an improvement in insulin sensitivity, a decrease in inflammatory factors, and increased incidence of adipocyte death. The consequences of modulation of angiogenic activity are therefore context dependent. Proangiogenic activity during adipose tissue expansion is beneficial, associated with potent protective effects on metabolism, whereas antiangiogenic action in the context of preexisting adipose tissue dysfunction leads to improvements in metabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes.

Key Words: neovascularization • VEGF receptor 2 • hypoxia • obesity


Author contributions: K.S., I.W.A., C.M.K., and P.E.S. designed research; K.S., I.W.A., C.M.K., and A.C.B. performed research; Z.V.W., J.W.P., and R.A.B. contributed new reagents/analytic tools; Z.V.W. generated the mouse model; K.S., I.W.A., C.M.K., and P.E.S. analyzed data; and K.S., I.W.A., C.M.K., and P.E.S. wrote the paper.

1I.W.A. and C.M.K. contributed equally to this work.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1200447109/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: philipp.scherer{at}utsouthwestern.edu.


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