Adipose Tissue Overexpression of Vascular Endothelial Growth Factor Protects Against Diet-Induced Obesity and Insulin Resistance

Abstract

During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance. Transgenic mice overexpressing vascular endothelial growth factor (VEGF) in brown adipose tissue (BAT) and white adipose tissue (WAT) were generated. Vessel formation, metabolism, and inflammation were studied in VEGF transgenic mice and wild-type littermates fed chow or a high-fat diet. Overexpression of VEGF resulted in increased blood vessel number and size in both WAT and BAT and protection against high-fat diet–induced hypoxia and obesity, with no differences in food intake. This was associated with increased thermogenesis and energy expenditure. Moreover, whole-body insulin sensitivity and glucose tolerance were improved. Transgenic mice presented increased macrophage infiltration, with a higher number of M2 anti-inflammatory and fewer M1 proinflammatory macrophages than wild-type littermates, thus maintaining an anti-inflammatory milieu that could avoid insulin resistance. These studies suggest that overexpression of VEGF in adipose tissue is a potential therapeutic strategy for the prevention of obesity and insulin resistance.

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 .…”

Effect of vascular endothelial growth factor receptor 2 antagonism on adiposity in obese mice

“…It is conceivable that VEGF/VEGF-R2 blockade and associated higher circulating VEGF levels in this model result in an improvement in glucose metabolism and in insulin signaling, as previously observed with ob/ob mice (Sun et al 2012). Furthermore, it was recently shown that overexpression of VEGF in the mouse was associated with improved whole body insulin sensitivity and glucose tolerance (Elias et al 2012). It was also reported that soluble VEGF-R2 is increased in sera of subjects with metabolic syndrome and insulin resistance (Wada et al 2012).…”

“…Furthermore, the VEGF/VEGF-R system may play a role in insulin resistance (Elias et al 2012). In this study, we have evaluated whether VEGF-R2 blockade affects adipose tissue-related angiogenesis and fat mass or insulin signaling in mice with established nutritionally induced obesity.…”

“…Furthermore, blockade of VEGF-R2 but not VEGF-R1 in mice was shown to limit diet-induced fat tissue expansion and suggested a role in early phase fat tissue development (Tam et al 2009). In addition, several studies have suggested a link between the VEGF/VEGF-R2 pathway and insulin sensitivity and glucose tolerance (Elias et al 2012, Wada et al 2010.…”