The role of VEGF signalling and the endothelium in metabolic dysfunction has become confused of late. While on the one hand targeted destruction of adipose endothelium results in the amelioration of insulin resistance and obesity, on the other hand, genetic over-expression of pro-angiogenic factors such as VEGF also ameliorates insulin resistance. To address this, we avoided genetic strategies, and instead used a VEGF-A neutralising antibody to reduce VEGF signalling. Treatment with this antibody rapidly reversed glucose intolerance and insulin resistance caused by high fat feeding. Hyperinsulinaemic euglycaemic clamps demonstrated that this was due almost entirely to changes in hepatic glucose output, suggesting that VEGF-A and alterations of the endothelium may exhibit protective effects depending on tissue context. As further evidence for the tissue dependent effects of endothelial alterations, over-expression of the NAD+ dependent deacetylase enzyme SIRT1 in the endothelium protects against age-dependent loss of capillaries in muscle, resulting in a doubling of running distance and improved glucose tolerance. Unlike the liver, protection of the endothelium in muscle may prevent the pseudohypoxic condition of aged muscle which underlies mitochondrial and metabolic dysfunction during old age.