Estrogen signaling and UCP1 : exploring mechanisms to improve metabolic health
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Metabolic disease risk rapidly escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through Estrogen Receptor a (ERa) which is highly expressed in brown (BAT) and white AT (WAT). Objective: Test the hypothesis that uncoupling protein (UCP1) activation via CL316, 243 effectively mitigates metabolic dysfunction due to loss of signaling through ERa. Methods: At 8 weeks of age, female ERa knock-out (KO) and wild-type (WT) mice were co-housed at 28 degree C and fed a Western high-fat diet for 10 weeks. They were given daily intraperitoneal injections of CL 316,243 (CL), a selective b3 adrenergicagonist, or vehicle control (CTRL) during the final two weeks, creating 4 groups: WT-CTRL, WT-CL, KO-CTRL, KO-CL; n=10/group. Comparisons were made for body weight (BW), adiposity (EchoMRI), food intake, energy expenditure (EE) and spontaneous physical activity (SPA) (metabolic chambers), insulin resistance (IR) (HOMA-IR, glucose area under the curve during insulin tolerance test (AUC)), and AT phenotype (histology, gene (rtPCR) and protein (Western blot) expression). Statistics: Two-way ANOVA for main effects of genotype (G), CL(T), and GxT interactions; significance set at P<0.05. Results: Fourteen days CL treatment increased AT UCP1 gene and protein expression in both WT and KO, and normalized ERaKO induced increases in BW and adiposity (both GxT, P<0.05) by increasing resting EE (REE/gBW) (T P<0.05) since neither energy intake (kcal/week/g BW) or SPA were affected. Higher HOMA-IR in ERaKO was normalized by CL, but unchanged in WT (GxT, P<0.05). Similarly, greater glucose AUC in KO (G P=0.01) was normalized, and also reduced in WT (T, P=0.018) with CL administration. CL did not reduce perigonadal (PGAT) inflammatory gene expression, which was greater in KO (Tnfa, Cd11c, F480; all G P<0.05), but did increase adiponectin and markers of mitochondrial biogenesis (Pgc1a, Tfam) in WT and KO (T, P<0.05). Conclusions: CL completely normalized metabolic dysfunction in ERaKO mice. UCP1 may be a therapeutic target for treating metabolic dysfunction following hormone loss. The mechanism appears independent of ERa availability and/or reduced AT inflammation.
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