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

Abstract

Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that ) in normal chow-fed mice housed at 25°C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only;) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and ) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions.

Increased susceptibility to OVX-associated metabolic dysfunction in UCP1-null mice

“…However, it is important to note that not all studies have supported that there is a sex difference in BAT content and/or activity (van der Lans et al 2013). In fact, when we compared BAT UCP1 levels in male and female mice (housed under the same temperature conditions as the present study), we did not find an increase in UCP1 protein content (Winn et al 2017a), although we did find greater UCP1 gene expression in females. Others have had similar findings in mice where no sex differences in BAT UCP1 content were found (Grefhorst et al 2015).…”

“…All mice were fed a standard chow diet (3.3 kcal/g of food, 13% kcal fat, 57% kcal carbohydrate and 30% kcal protein, 5001, LabDiet, St. Louis, MO, USA) and were housed two to three per cage (within group) in a light cycle from 07:00 to 19:00 h at 25°C. In previous studies, these conditions were shown to be adequate in preventing thermostress (Winn et al 2017a). WT and UCP1KO female mice underwent OVX or sham (SHM) operations at 12 weeks of age creating four distinct groups (n = 10/group): (1) WT SHM, (2) WT OVX, (3) KO SHM and (4) KO OVX.…”

“…Tissues were harvested and either fixed in 10% formalin, snap-frozen in liquid nitrogen and stored at −80°C until analyses. Data were generated from a subset of these animals in a previous study (Winn et al 2017a).…”

A dual Ucp1 reporter mouse model for imaging and quantitation of brown and brite fat recruitment

“…In rats, females have significantly higher UCP1 abundance in BAT than males, though these sex-associated divergences disappear or reverse during cold- and diet-induced thermogenesis [22], [24], [25]. Despite higher Ucp1 mRNA levels in interscapular BAT (iBAT) of female mice [26], there are no significant sex differences in UCP1 protein levels in iBAT or inguinal WAT (iWAT) [26], [27]. Regarding these conflicting data, sexual dimorphism in Ucp1 gene expression and thermogenic capacity and activity of brown and brite fat in different anatomical regions requires further investigation.…”

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of β-adrenergic activation

“…Accordingly, comparisons are made within the artery, limiting the inherent between-artery and between-animal variability. Aortic rings were mounted in wire myograph organ bath chambers (620 M, Danish Myo Technology, Hinnerup, Denmark) containing warmed physiological saline solution gassed with 95% O 2 -5% CO 2 and maintained at 37 C as previously described (43,44). Aortic rings were treated with 80 mM KCl to ensure viability.…”