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Front. Physiol. | doi: 10.3389/fphys.2019.00009

Beta 3 Adrenergic Receptor Activation Rescues Metabolic Dysfunction in Female Estrogen Receptor Alpha-Null Mice

Stephanie L. Clookey1, Rebecca J. Welly1,  Dusti Shay1,  Makenzie L. Woodford1,  Kevin L. Fritsche1,  R S. Rector1, 2, 3,  Jaume Padilla1, 4, 5, Dennis B. Lubahn6 and  Victoria J. Vieira Potter1*
  • 1Department of Nutrition and Exercise Physiology, University of Missouri, United States
  • 2Harry S. Truman Memorial Veterans' Hospital, United States
  • 3School of Medicine, University of Missouri, United States
  • 4Dalton Cardiovascular Research Center, University of Missouri, United States
  • 5Department of Child Health, School of Medicine, University of Missouri, United States
  • 6Department of Biochemistry, University of Missouri, United States

Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ER), which is highly expressed in brown and white adipose tissue (BAT, WAT). Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ER. Methods: At 8 weeks of age, female ER 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 two weeks, they received daily injections of CL 316,256 (CL), a selective 3 adrenergic agonist, or vehicle control (CTRL), creating 8 groups: WT-CTRL, WT-CL, KO-CTRL, KO-CL on HFD or NC; n=4-10/group. Results: ERKO 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 ERKO-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 ER protein levels of both WT and KO (P<0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects. Conclusions: CL completely restored metabolic dysfunction in ERKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling.

Keywords: Adipose Tissue, Energy expenditure (EE), Browning activity, Insuliin resistance, High fat diet (HFD), CL 316, 243, Obesity, rodent

Received: 04 Oct 2018; Accepted: 08 Jan 2019.

Edited by:

Rita De Matteis, University of Urbino Carlo Bo, Italy

Reviewed by:

Alexandre Caron, University of Texas Southwestern Medical Center, United States
Ismael González-García, Helmholtz Center Munich - German Research Center for Environmental Health, Germany
Bin Feng, Sichuan Agricultural University, China  

Copyright: © 2019 Clookey, Welly, Shay, Woodford, Fritsche, Rector, Padilla, Lubahn and Vieira Potter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Victoria J. Vieira Potter, Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, 65211, Kentucky, United States, vieirapotterv@missouri.edu