To answer these questions we examined (1) the temporal changes in expression of IGF-1R, IR and hybrids in aorta and their correlates in high-fat diet-induced obesity; (2) the effect of different pathological insults associated with obesity on IGF-1R, IR and hybrid expression in human endothelial cells; and (3) the effect of IGF-1 and insulin on resistance vessel tone and Akt phosphorylation and the influence of obesity on these responses. The gene discussed is IGF1R; the disease is obesity due to melanocortin 4 receptor deficiency.