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.