Loss of UCP1 improves ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction

Abstract

Female rodents are more insulin sensitive than males which may be partly attributed to greater brown adipose tissue (AT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that loss of UCP1 would produce greater metabolic disturbances in females than males such that sex differences in insulin sensitivity would be abolished. Furthermore, we hypothesized that whitening of thoracic periaortic brown AT caused by UCP1 deletion would be accompanied with impaired thoracic aortic function. Last, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency‐induced metabolic dysfunction is mediated by oxidative stress. Compared to males, female mice had lower glucose and HOMA‐ and AT‐insulin resistance (IR) despite no differences in UCP1 protein content in interscapular brown AT. UCP1 ablation caused similar increases in HOMA‐IR and AT‐IR in both female and male mice such that no sex x genotype interactions were evident. In spite of UCP1 loss‐induced IR and whitening of thoracic periaortic brown AT, UCP1 knockout female mice exhibited improved aortic vasomotor function. Moreover, UCP1 ablation did not produce increased interscapular brown AT oxidative stress. Similarly, administration of the free radical scavenger Tempol for 8 weeks in drinking water did not abrogate lack of UCP1‐induced increases in adiposity, hyperinsulinemia, or liver steatosis. Taken together, our findings indicate that 1) loss of UCP1 provokes similar induction of IR in female and male mice; 2) paradoxically, deletion of UCP1 improves ex vivo aortic vasomotor function in female but not male mice; and 3) the metabolic disruptions caused by UCP1 ablation are not contingent upon increased oxidative stress.