Abstract
It has been shown that adipose tissue and skeletal muscles in lean individuals respond to meal-induced hyperinsulinemia by increase in perfusion, the effect not observed in patients with metabolic syndrome. In conditions of hyperglycaemia and hypertriglyceridemia, this insufficient vascularization leads to the liberation of reactive oxygen species (ROS), and disruption of nitric oxide (NO) synthesis and endothelial signalling responsible for the uptake of circulating fatty acids (FAs), whose accumulation in skeletal muscles and adipose tissue is widely associated with the impairment of insulin signalling. While the angiogenic role of VEGF-A and its increased circulating concentrations in obesity have been widely confirmed, the data related to the metabolic role of VEGF-B are diverse. However, recent discoveries indicate that this growth factor may be a promising therapeutic agent in patients with metabolic syndrome. Preclinical studies agree over two crucial metabolic effects of VEGF-B: (i) regulation of FAs uptake and (ii) regulation of tissue perfusion via activation of VEGF-A/vascular endothelial growth factor receptor (VEGFR) 2 (VEGFR2) pathway. While in some preclinical high-fat diet studies, VEGF-B overexpression reverted glucose intolerance and stimulated fat burning, in others it further promoted accumulation of lipids and lipotoxicity. Data from clinical studies point out the changes in circulating or tissue expression levels of VEGF-B in obese compared with lean patients. Potentially beneficial effects of VEGF-B, achieved through enhanced blood flow (increased availability of insulin and glucose uptake in target organs) and decreased FAs uptake (prevention of lipotoxicity and improved insulin signalling), and its safety for clinical use, remain to be clarified through future translational research.
Highlights
The worldwide pandemic of obesity associated with net positive energy balance, sedentary lifestyle and increased consumption of animal fats, processed food and sugar has brought to forefront the need for novel therapeutic strategies to protect against the metabolic disturbances in such context [1]
Supposing that Hagberg et al [3] correctly hypothesized that vascular endothelial growth factor (VEGF)-B produced by skeletal muscle leads to expression of endothelial Fatp3 and Fatp4, initiating transendothelial transport of fatty acid (FA) into the muscle fibres in high-fat diets and obesity, it would be reasonable to expect that decreased VEGF-B expression prevents lipid accumulation in skeletal muscle
If the binding of VEGF-B to VEGF receptor 1 (VEGFR1) activates the VEGF-A/VEGF receptor 2 (VEGFR2) pathway increasing capillary density, tissue perfusion and insulin supply and signalling by the mechanism proposed by Robciuc et al [32], it would be to expect that circulating levels of VEGF-B in obese patients are increased as well
Summary
The worldwide pandemic of obesity associated with net positive energy balance, sedentary lifestyle and increased consumption of animal fats, processed food and sugar has brought to forefront the need for novel therapeutic strategies to protect against the metabolic disturbances in such context [1]. Supposing that Hagberg et al [3] correctly hypothesized that VEGF-B produced by skeletal muscle leads to expression of endothelial Fatp3 and Fatp4, initiating transendothelial transport of FAs into the muscle fibres in high-fat diets and obesity, it would be reasonable to expect that decreased VEGF-B expression prevents lipid accumulation in skeletal muscle.
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