Abstract
Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ERα), which is highly expressed in brown and white adipose tissue (BAT and WAT).Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ERα.Methods: At 8 weeks of age, female ERα knock out (KO) and wild-type mice were housed at 28°C and fed a Western-style high-fat, high sucrose diet (HFD) or a normal low-fat chow diet (NC) for 10 weeks. During the final 2 weeks, they received daily injections of CL 316,256 (CL), a selective β3 adrenergic agonist, or vehicle control (CTRL), creating eight groups: WT-CTRL, WT-CL, KO-CTRL, and KO-CL on HFD or NC; n = 4–10/group.Results: ERαKO demonstrated exacerbated HFD-induced adiposity gain (P < 0.001) and insulin resistance (P = 0.006). CL treatment improved insulin sensitivity (P < 0.05) and normalized ERαKO-induced adiposity increase (P < 0.05). In both genotypes, CL increased resting energy expenditure (P < 0.05) and induced WAT beiging indicated by increased UCP1 protein in both perigonadal (PGAT) and subcutaneous (SQAT) depots. These effects were attenuated under HFD conditions (P < 0.05). In KO, CL reduced HFD energy consumption compared to CTRL (P < 0.05). Remarkably, CL increased WAT ERβ protein levels of both WT and KO (P < 0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects.Conclusion: CL completely restored metabolic dysfunction in ERαKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling.
Highlights
Compared to males, ovary-intact females are protected against obesity and its associated metabolic consequences, including insulin resistance, which precedes diabetes onset (Brand et al, 2012)
uncoupling protein 1 (UCP1) may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling
The increase in those surrogate markers of insulin resistance were primarily driven by hyperinsulinemia in the ERaKOs in response to high fat diet (HFD); ERaKOs fed HFD exhibited a fourfold increase in fasting insulin compared to normal low-fat chow diet (NC) (G×D, P = 0.036) (Table 2)
Summary
Ovary-intact females are protected against obesity and its associated metabolic consequences, including insulin resistance, which precedes diabetes onset (Brand et al, 2012). Adipose tissue is heavily influenced by estrogen (Ogden et al, 2012; Davis et al, 2013) and is an important target tissue to improve metabolic health. Pinpointing what factors protect female adipose tissue prior to menopause could have tremendous implications for women’s health. In this regard, the protection against adipose tissue dysfunction is likely due to adipocyte-specific estrogen signaling (D’Eon et al, 2005; Mauvais-Jarvis et al, 2013; Kim et al, 2014; Luglio, 2014) through estrogen receptor alpha (ERα) (Davis et al, 2013). Directly decreasing adipocyte ERα signaling causes adipocyte dysfunction (Davis et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
