Premenopausal females are protected against adipose tissue inflammation and insulin resistance, until loss of ovarian hormone production (e.g., menopause). There is some evidence that females have greater brown adipose tissue (BAT) thermogenic capacity. Because BAT mass correlates inversely with insulin resistance, we hypothesized that increased uncoupling protein 1 (UCP1) expression contributes to the superior metabolic health of females. Given that UCP1 transiently increases in BAT following ovariectomy (OVX), we hypothesized that UCP1 may ‘buffer’ OVX-mediated metabolic dysfunction. Accordingly, female UCP1-knockout (KO) and WT mice received OVX or sham (SHM) surgeries at 12 weeks of age creating four groups (n = 10/group), which were followed for 14 weeks and compared for body weight and adiposity, food intake, energy expenditure and spontaneous physical activity (metabolic chambers), insulin resistance (HOMA-IR, ADIPO-IR and glucose tolerance testing) and adipose tissue phenotype (histology, gene and protein expression). Two-way ANOVA was used to assess the main effects of genotype (G), OVX treatment (O) and genotype by treatment (GxO) interactions, which were considered significant when P ≤ 0.05. UCP1KO mice experienced a more adverse metabolic response to OVX than WT. Whereas OVX-induced weight gain was not synergistically greater for KO compared to WT (GxO, NS), OVX-induced insulin resistance was significantly exacerbated in KO compared to WT (GxO for HOMA-IR, P < 0.05). These results suggest UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones and support the need for more research into therapeutics to selectively target UCP1 for prevention and treatment of metabolic dysfunction following ovarian hormone loss.
Supplemental Figure 1. Effects of OVX and UCP1 ablation on body weight gain and subcutaneous adipose tissue gene expression. UCP1 null and wild-type female mice were given an ovariectomy or sham surgery at 12 weeks of age, then sacrificed after 14 weeks. Body weight was assessed weekly pre and post ovariectomy surgery, for a total of 25 weeks, and upon sacrifice, subcutaneous adipose tissue was harvested and processed for gene expression: (A) body weight gain over time (B) subcutaneous adipose tissue gene expression. 2x2 analysis of variance (ANOVA) was performed to assess main effects of genotype (G), treatment (O), and genotype and treatment interactions (GxO). GxO were followed by Tukey’s post hoc tests. Where such tests revealed significant differences between groups, those differences are indicated. Data are expressed as means ± standard error (SE); n=10/group, significance was accepted at P<0.05.