Dichotomous effects of VEGF-A on adipose tissue dysfunction

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.

Control of Adipose Tissue Expandability in Response to High Fat Diet by the Insulin-like Growth Factor-binding Protein-4

“…Hypoxia-induced pro-angiogenic factors such as VEGF would then stimulate angiogenesis, thus enhancing blood and oxygen supply and reducing hypoxia in the expanded tissue. This possibility is supported by the finding that adipocytes can secrete numerous potent pro-angiogenic factors, some in response to hypoxia (11), and that VEGF-A expression can mitigate the development of metabolic dysfunction in response to a high fat diet (HFD) 2 (12,13). However, recent studies suggest that hypoxia of adipose tissue may not reach levels sufficient to elicit a pro-angiogenic response (14) and that expression of HIF-1␣ in adipocytes results in fibrosis rather than angiogenesis (15).…”

Brown and beige fat: development, function and therapeutic potential

“…In cultured brown adipocytes, Vegf enhanced cell survival and proliferation, whereas VEGF-neutralizing antibodies caused apoptosis 92 . Notably, overexpression of Vegf in adipose tissues of mice increases BAT mass, stimulates beiging and promotes a healthy metabolic profile 93,94 . Vegf inhibition has also been shown to reduce metabolic disease in mice, although this effect was in the context of obese WAT that was already dysfunctional 94,95 .…”

“…Notably, overexpression of Vegf in adipose tissues of mice increases BAT mass, stimulates beiging and promotes a healthy metabolic profile 93,94 . Vegf inhibition has also been shown to reduce metabolic disease in mice, although this effect was in the context of obese WAT that was already dysfunctional 94,95 . Further studies will be needed to elucidate the mechanism(s) by which VEGF manipulates the fate of adipose tissue under different metabolic states.…”

The PPARγ-FGF1 axis: an unexpected mediator of adipose tissue homeostasis

“…As a result, the free fatty acid release into circulation is increased and causes abnormal ectopic lipid accumulation in other tissues [1], including a significant elevation of hepatic steatosis in the FGF1-knockout mice [10]. Taken together, this cluster of phenotypic changes reported in response to the unhealthy fat tissue expansion in FGF1-knockout mice has been reported in other mouse models as well [3,12,14]. Notably, most dramatic functional deficiencies happen specifically in gWAT.…”

“…Our group recently demonstrated the importance of fully functional pro-angiogenic pathways for healthy fat pad remodeling. We achieved this by adipocyte-specific VEGF overexpression during a HFD challenge [12]. Since angiogenesis is a rate-limiting step during adipose tissue expansion [1], and since FGF1 has been reported to function as a modifier of endothelial cell migration and proliferation and has hence been postulated to be an angiogenic factor [13], Jonker and colleagues examined the vasculature in white adipose tissue (WAT) of Fgf -/-mice.…”