Suppression of estrogen receptor beta classical genomic activity enhances systemic and adipose-specific response to chronic beta-3 adrenergic receptor (β3AR) stimulation

• Published in: Frontiers in physiology 2022-09, Vol.13, p.920675-920675
• Main Authors: Queathem, Eric D, Fitzgerald, Maggie, Welly, Rebecca, Rowles, Candace C, Schaller, Kylie, Bukhary, Shahad, Baines, Christopher P, Rector, R Scott, Padilla, Jaume, Manrique-Acevedo, Camila, Lubahn, Dennis B, Vieira-Potter, Victoria J
• Format: Article
• Language: English
• Subjects: adipocyte browning; adipocyte mitochondria; energy expenditure; estrogen signaling; insulin resistance; Physiology
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2022.920675

White adipose tissue (WAT) dysfunction independently predicts cardiometabolic disease, yet there is a lack of effective adipocyte-targeting therapeutics. B3AR agonists enhance adipocyte mitochondrial function and hold potential in this regard. Based on enhanced sensitivity to B3AR-mediated browning in estrogen receptor (ER)alpha-null mice, we hypothesized that ERβ may enhance the WAT response to the B3AR ligand, CL316,243 (CL). Male and female wild-type (WT) and ERβ DNA binding domain knock-out (ERβ KO) mice fed high-fat diet (HFD) to induce obesity were administered CL (1 mg/kg) daily for 2 weeks. Systemic physiological assessments of body composition ( ), bioenergetics ( ), adipocyte mitochondrial respiration ( ) and glucose tolerance were performed, alongside perigonadal (PGAT), subcutaneous (SQAT) and brown adipose tissue (BAT) protein expression assessment ( ). Mechanisms were tested using primary adipocytes isolated from WT mice, and from Esr2-floxed mice in which ERβ was knocked down. Statistical analyses were performed using 2 × 2 analysis of variance (ANOVA) for main effects of genotype (G) and treatment (T), as well as GxT interactions; t-tests were used to determine differences between treatment conditions (SPSS V24). There were no genotype differences in HFD-induced obesity or systemic rescue effects of CL, yet ERβ KO females were more sensitive to CL-induced increases in energy expenditure and WAT UCP1 induction (GxT, < 0.05), which coincided with greater WAT B3AR protein content among the KO (G, < 0.05). Among males, who were more insulin resistant to begin with (no genotype differences before treatment), tended to be more sensitive to CL-mediated reduction in insulin resistance. With sexes combined, basal WAT mitochondrial respiration trended toward being lower in the ERβ KO mice, but this was completely rescued by CL ( < 0.05). Confirming prior work, CL increased adipose tissue ERβ protein (T, < 0.05, ) an effect that was enhanced in WAT and BAT the female KO (GxT, < 0.01). experiments indicated that an inhibitor of ERβ genomic function (PHTPP) synergized with CL to further increase UCP1 mRNA ( = 0.043), whereas full ERβ protein was required for UCP1 expression ( = 0.042). Full ERβ activity appears requisite and stimulatory for UCP1 expression via a mechanism involving non-classical ERβ signaling. This novel discovery about the role of ERβ in adipocyte metabolism may have important clinical applications.