UCP1‐Null Mice Display Increased Susceptibility to Ovariectomy‐Associated Metabolic Dysfunction
Authors: Clookey Stephanie L. , Welly Rebecca J. , Zidon Terese M. , Gastecki Michelle L. , Grunewald Zachary I. , Winn Nathan C. , Karasseva Natalia G. , Sacks Harold S. , Padilla Jaume , Vieira‐Potter Victoria Jeanne 
Published: November 2023

Compared to males, females are protected against adipose inflammation and insulin resistance (IR), major predictors of metabolic disease, until they experience loss of ovarian hormone production (e.g., menopause). Several studies implicate estrogen loss being primarily responsible for this protection, but the mechanisms are not known. Better understanding those mechanisms would have important health implications for both sexes. Females have greater brown adipose tissue (BAT) with increased expression of uncoupling protein 1 (UCP1), its signature protein. Because BAT, and upregulation of UCP1 in white adipose tissue (WAT), correlates inversely with IR, and prior studies have shown increased susceptibility for metabolic dysfunction with decreased BAT, we hypothesized that increased UCP1 expression may be mechanistically related to the greater metabolic protection observed in females. Our finding that UCP1 transiently increases in BAT following ovariectomy (OVX) led us to hypothesize that this compensatory response buffers OVX‐mediated metabolic dysfunction. As such, the purpose of this study was to investigate whether UCP1 knock‐out (KO) mice would experience exacerbated metabolic dysfunction following OVX compared to wild‐type (WT) controls. Female UCP1KO and WT mice received OVX or sham (SHM) surgeries at 16 weeks of age creating 4 groups (C57Bl6J background; n=10/group, housed at 25°C), which were followed for 14 weeks and finally compared for: body weight and adiposity gain (EchoMRI, depot weights), food intake, energy expenditure (EE) and spontaneous physical activity (SPA) (metabolic chambers), IR (HOMA‐IR, Adipo‐IR, and glucose tolerance test), and interscapular BAT phenotype (histology, gene expression via rtPCR). Statistics: 2‐way ANOVA for main effects of genotype (G), treatment (T), and GXT interactions considered significant when P<0.05. Main G effects were found for: increased BAT and WAT mass (both, P<0.01), BAT endoplasmic reticulum stress (increased ddit3, P<0.05), and increased Adipo‐IR (P<0.02). Main effects of T were found for decreased EE, SPA, food intake, and relative BAT mass (all P<0.05). However, KO mice experienced a more adverse metabolic response to OVX than WT, since OVX‐induced weight gain was ~5% greater in KO compared to WT (int trend, P=0.056) and there was a significant GXT interaction on HOMA‐IR (P<0.05), with OVX/KO having the worst scores. Those data paralleled GXT interactions for BAT adipokines, leptin (increased in OVX/KO) and adiponectin (decreased in OVX/KO) (both int P<0.05) and found OVX increased BAT UCP1 mrRNA in WT (GXT P<0.05). These results suggest AT UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones, opening the possibility that it may serve as a therapeutic target in those settings.

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