VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications

Abstract

SUMMARY Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway.

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

“…S2). This is in line with our previously published findings on VEGF-B levels in different tissues after systemic AAV9 delivery (12).…”

“…The highest endogenous concentrations of VEGF-B are found in cardiomyocytes (9). Exogenous VEGF-B is a potent arteriogenic growth factor that can promote physiological cardiac hypertrophy and counteract metabolic problems of obesity (10)(11)(12). Furthermore, reduced VEGF-B expression occurs in dilated cardiomyopathy and…”

White adipose tissue coloring by intermittent fasting

“…VEGF-VEGFR2 pathway activation is induced indirectly by VEGF-B, which displaces VEGF from VEGFR1. An excess of VEGF-B was recently shown to result in increased adipose vasculature, beiging of WAT and increased energy expenditure, leading to improved metabolic health in mice [5]. These effects of VEGF-B were limited by the endogenous VEGF levels; thus, it appears to be a safer approach than VEGF delivery for VEGFR2 activation in vivo.…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…Robciuc 64 et al. implied the promise of VEGF-B transgenic or VEGF-B protein delivery to ameliorate insulin sensitivity (to improve insulin sensitivity or to ameliorate insulin resistance), diminishes obesity, and alleviate metabolic syndrome, by displacing VEGF-A from VEGFR-1 to activate VEGFR-2 and increasing adipose tissue vascularity, thereupon providing a therapeutic tactics for counteracting obesity.…”

“…59 The contradiction aroused that how to settle the discrepancies between the two studies. 13 , 64 We compared, in order to make them seem harmonious. (i) The insulin resistance in the two studies was derived from the insufficient vascularization and consecutive hypoxia and the ectopic fat accumulation, thus the VEGF-B linked downstream angiogenic event and the suppression of the VEGF-B medicated lipids trafficking could help, respectively.…”