Transgenic overexpression of VEGF-C induces weight gain and insulin resistance in mice.

Sinem Karaman,Michael Detmar,Kari Alitalo,Sun-Young Yoon,H Furkan Alkan,Maija Hollmén,Christian Wolfrum

doi:10.1038/srep31566

Abstract

Obesity comprises great risks for human health, contributing to the development of other diseases such as metabolic syndrome, type 2 diabetes and cardiovascular disease. Previously, obese patients were found to have elevated serum levels of VEGF-C, which correlated with worsening of lipid parameters. We recently identified that neutralization of VEGF-C and -D in the subcutaneous adipose tissue during the development of obesity improves metabolic parameters and insulin sensitivity in mice. To test the hypothesis that VEGF-C plays a role in the promotion of the metabolic disease, we used K14-VEGF-C mice that overexpress human VEGF-C under control of the keratin-14 promoter in the skin and monitored metabolic parameters over time. K14-VEGF-C mice had high levels of VEGF-C in the subcutaneous adipose tissue and gained more weight than wildtype littermates, became insulin resistant and had increased ectopic lipid accumulation at 20 weeks of age on regular mouse chow. The metabolic differences persisted under high-fat diet induced obesity. These results indicate that elevated VEGF-C levels contribute to metabolic deterioration and the development of insulin resistance, and that blockade of VEGF-C in obesity represents a suitable approach to alleviate the development of insulin resistance.

Highlights

The rising incidence of overweight and obesity worldwide has become one of the principal global public health issues of the 21st century[1]
Preferential transgene production in the skin was confirmed by the detection of transgenic human VEGF-C (hVEGF-C) in the subcutaneous white adipose tissue (SWAT) (25.4 pg hVEGF-C/ mg protein), that is in close proximity to the skin, of K14-Vascular endothelial growth factors (VEGFs)-C mice, whereas serum hVEGF-C levels were below detection limit, potentially due to the short half-life of VEGF-C in blood[17] (Supplementary Fig. S1)
Our findings reveal that transgenic overexpression of VEGF-C in mice induces a moderate yet significant weight gain, adipocyte hypertrophy, ectopic lipid accumulation in the liver and insulin resistance under both diets via recruitment of inflammatory macrophages into adipose tissue

Summary

Introduction

The rising incidence of overweight and obesity worldwide has become one of the principal global public health issues of the 21st century[1]. In-depth studies in this field indicate that obesity-induced metabolic inflammation in adipose tissue is one of the main contributors to the development of insulin resistance, creating a new niche for metabolic research, i.e. Chronic low-grade inflammation and an increase in inflammatory cytokine levels in the adipose tissue during obesity play a critical role in attracting proinflammatory cells –especially macrophages– into the SVF compartment[5,6]. We found that both transgenic and antibody-mediated blockade of VEGF-C/D signaling in subcutaneous adipose tissue of mice reduced inflammatory macrophage infiltration, inflammatory cytokine expression and hepatic steatosis, and improved insulin sensitivity in both diet-induced and genetic obesity[12]. Our results reveal that elevated VEGF-C levels in subcutaneous adipose tissue contribute to the development of adipocyte hypertrophy, ectopic lipid accumulation and insulin resistance

Methods

Results

Conclusion