An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice

Abstract

Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERβ agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα−/− female mice. Browning was associated with increased expression of ERβ in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of β3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERβ in the SAT and very little expression of the β3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERβ in controlling browning of adipose tissue.

Absence of estrogen receptor beta leads to abnormal adipogenesis during early tendon healing by an up‐regulation of PPARγ signalling

“…21,48 LY 3201 is one of the specific agonists of ERβ that has been proved to effectively and characteristically activate ERβ but not α that renders it of great clinical application value. 16 Consistent with the in vivo findings, our in vitro results showed that activation of ERβ 21,49 Thus, on the one hand, ERβ absence leads to more adipocyte differentiation during early healing process which interrupts ideal repair. On the other hand, whether increased adipocyte differentiation inhibits tenocyte differentiation needs further investigation.…”

The role of estrogens in the adipose tissue milieu

“…In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency. In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency.…”

“…While the mechanisms by which signaling through ERβ may have antiobesity effects are not clear, new evidence implicates ERβ as a primary mediator of 17β-E2's protective metabolic effects regarding adipose tissue mitochondrial activity. In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency. 150 A major caveat is that the majority of these studies investigating isotype-specific effects of ER signaling have been done in rodent models, not humans.…”

Estrogen Receptor beta (ERβ) Regulation of Lipid Homeostasis—Does Sex Matter?

“…It has been demonstrated that estrogens are involved in the regulation of metabolic processes by investigating the actions of ERα and ERβ using appropriate models lacking either ERα (αERKO) [10] or ERβ (βERKO) [11,12]. Aromatase knockout (ArKO) [13] or ovariectomized (OVX) [14] mice are also models that are frequently used in research on estrogen receptor signaling due to loss of, or reduced, circulating estrogens.…”

“…Moreover, the activation of ERs by synthetic ligands/agonists is another approach used in endocrinology studies in both males and females that may better reflect human physiology. A large number of ERβ-selective ligands including DPN [11], WAY200070 [15], β-LGNDs [8,12], LY3201 [10] and DIP [6,9] have been used to further investigate the role of ERβ in metabolic homeostasis.…”