Dichotomous

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 SurgicalOncology, 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)
Obese fat pads are frequently undervascularized and hypoxic, lead- ing to increased fibrosis, inflammation, and ultimately insulin re- sistance. We hypothesized that VEGF-A–induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrientexchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-spe- cific 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 mas- sive up-regulation of UCP1 and PGC1α. This is associated with an increase in energyexpenditure and resistance to high fat diet-me- diated metabolic insults. Similarly, inhibition of VEGF-A–induced activation of VEGFR2 during the early phase of high fat diet-in- duced 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 sensi- tivity, a decrease ininflammatory 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 po- tent protective effects on metabolism, whereas antiangiogenic ac- tion in the context of preexisting adipose tissue dysfunction leads to improvements inmetabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes.
neovascularization | VEGF receptor 2 | hypoxia | obesity
Adipose tissue (AT) has unique plasticity, illustrated by its ability for rapid and dynamic expansion or reduction in periods of excess energy exposure or demand to ensure proper systemic energy homeostasis. AT expansion includes both hyper- trophicand hyperplastic growth (1, 2). During the progression to chronic obesity, AT depots undergo profound pathological changes (3), such as enhanced oxidative damage, ER stress, local hypoxia, fibrosis, as well as immune cell infiltration and in- flammation; many of these changes ultimately promote the de- velopment of insulin resistance (3).
However, not all AT expansion is associated withpathological changes. A subgroup of individuals that we refer to as “metabol- ically healthy obese” manage to expand their AT mass without the associated pathological consequences. The concept of “healthy AT expansion” suggests that fat pads differ largely with respect to how well they cope with the local tissue growth (3). In contrast to the pathological expansion widely seen upon weight gain, a healthyexpansion consists of an enlargement of a given fat pad through recruitment of new adipocytes, along with the adequate de- velopment of the vasculature, minimal associated fibrosis, and the lack of hypoxia and inflammation (3).
AT is a highly vascularized tissue. Almost all adipocytes are surrounded by capillaries (4). A functional vascular system is critical for AT expansion. The macro- and...