Resistance to Obesity by Repression of VEGF Gene Expression through Induction of Brown-Like Adipocyte Differentiation

Abstract

Adipose tissues are classified into white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for energy storage, and malfunction is associated with obesity. BAT, on the contrary, consumes fat to generate heat through uncoupling mitochondrial respiration and is important in body weight control. Vascular endothelial growth factor (VEGF)-A is the founding member of the VEGF family and has been found highly expressed in adipose tissue. A genetic mouse model of an inducible VEGF (VEGF-A) repression system was used to study VEGF-regulated energy metabolism in WAT. VEGF-repressed mice demonstrated lower food efficiency, lower body weight, and resistance to high-fat diet-induced obesity. Repression of VEGF expression caused morphological and molecular changes in adipose tissues. VEGF repression induced brown-like adipocyte development in WAT, up-regulation of BAT-specific genes including PRDM16, GATA-1, BMP-7, CIDEA, and UCP-1 and down-regulation of leptin, a WAT-specific gene. VEGF repression up-regulated expression of VEGF-B and its downstream fatty acid transport proteins. Relative levels of VEGF/VEGF-B may be important switches in energy metabolism and of pharmaceutical significances.

Brown and beige fat: development, function and therapeutic potential

“…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.…”

Systemic VEGF-A Neutralization Ameliorates Diet-Induced Metabolic Dysfunction

“…Serum levels of VEGF-A are raised during obesity (9)(10)(11) and rapidly decrease following bariatric surgery (10), suggesting that elevated VEGF is deleterious. In support of this Lu et al (12) showed that VEGF knockdown suppressed obesity and promoted "browning" of white adipose tissue (WAT). In contrast, reports using adipose-specific VEGF transgenic or knockout mice suggest that increased expression of VEGF is beneficial during obesity (12)(13)(14)(15).…”

“…In support of this Lu et al (12) showed that VEGF knockdown suppressed obesity and promoted "browning" of white adipose tissue (WAT). In contrast, reports using adipose-specific VEGF transgenic or knockout mice suggest that increased expression of VEGF is beneficial during obesity (12)(13)(14)(15). This is further complicated by contradictory reports depending on the model system; Sun et al (13) found that antibody neutralization of VEGF impaired metabolic homeostasis in a dietary model of obesity but improved glucose tolerance in a genetic (ob/ob) model.…”

Vascular endothelial growth factor induces anti-Müllerian hormone receptor 2 overexpression in ovarian granulosa cells of in vitro fertilization/intracytoplasmic sperm injection patients

“…The specificity of amplification was confirmed by melting curve analysis and gel electrophoresis. All results were normalized to the levels of 18S ribosomal (r)RNA, and relative quantification was calculated using relative quantification (ΔΔCq) values for each biological replicate (16,17). Values are expressed as the mean ± standard error of the mean (SEM; triplicate samples and three repeats).…”