Activation of estrogen receptor alpha induces beiging of adipocytes

Abstract

ObjectivesBrown adipose tissue (BAT) and BAT-like adipose tissues, referred to as ‘beige’ adipose tissues uncouple respiration from ATP synthesis via uncoupling protein one (UCP-1). There is a sexual dimorphism with respect to beige and BAT tissues; pre-menopausal women have more BAT and are more sensitive to BAT activation than men or postmenopausal women. We hypothesized selective activation of adipose tissue estrogen receptor alpha (ERα) induces beiging of WAT through induction of lipolysis mediated by adipose tissue triglyceride lipase (ATGL).Methods3T3-L1 and primary adipocytes were treated with the selective ERα agonist pyrazole triol (PPT), and selection deletion of ERα (using siRNA) was used to determine if selective ERα activation, or inhibition, influences the adipose tissue expression of genes associated with beiging. In a second series of experiments, ERα was selectively added back to adipose tissue of mice lacking total body ERα (ERKO) to determine if add back of ERα changed the morphology of adipose tissue to resemble beige tissues. Additionally, WT and ERKO mice were exposed to cold and FDG labeled glucose uptake was measured to determine the ability of cold to induce UCP-1 in ERKO mice. To begin to mechanistically probe how activation of ERα facilitates beiging, we tested the influence of PPT to activate the lipolytic pathway through ATGL. Finally, since ERα exerts its effects both at the genomic and non-genomic level depending on its cellular location, we determined in vivo if beiging occurs in mice expressing ERα only at the plasma membrane (MOER mice) or only at nucleus (NOER mice).ResultsSelective ERα activation by PPT increased markers of beiging in vitro in 3T3-L1 and primary adipocytes, whereas, knockdown of ERα with siRNA reduced the ability of PPT to induce beiging in vitro. ERα add back to the adipose tissue of ERKO mice resulted in multilocular adipose tissue resembling a beige phenotype. Following cold exposure, FDG labeled glucose in BAT tissues of ERKO mice was reduced when compared to weight-matched controls. Glycerol release and ATGL expression were increased after PPT treatment, while pre-treatment with the ATGL inhibitor prevented PPT's ability to increase UCP-1 expression. Finally, MOER mice were more sensitive to beiging of adipose tissues when compared to NOER mice.ConclusionOur results demonstrate for the first time that selective-activation of ERα in adipocytes increases markers of beiging and this is likely through induction of AMPK and ATGL-mediated lipolysis providing FFAs as a fuel to activate UCP-1.

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided

“…OCR was measured every 8.5 min for 400 min. To demonstrate the effect of lipolysis we added 20 μM ATGL inhibitor Atglinstatin (Sigma-Aldrich) as described previously [ 51 ], with 0.5 AM6545 or 0.5 mM RIM. The real-time measurements were performed for 400 min.…”

Sex differences in metabolic regulation and diabetes susceptibility

“…In line with this observation, oestrogens have recently been demonstrated to enhance thermogenesis in brown adipose tissue and to promote beiging of white adipocytes. Indeed, in vitro and in vivo approaches have demonstrated that selective activation of ERα induces adipose tissue beiging through induction of AMP-activated protein kinase (AMPK) and adipose triglyceride lipase (ATGL)-mediated lipolysis, resulting in NEFA generation and uncoupling protein 1 (UCP-1) activation [29]. Finally, as revealed by 18 F-fluoro-2-deoxy-d-glucose ( 1 8 F-FDG) positron-emission tomography-computed tomography (PET-CT) scanning, brown adipose tissue is better preserved and more metabolically active in women than in men, thus contributing to enhanced energy expenditure in the former [30,31].…”

Obesity induced by estrogen deficiency is associated with hypothalamic inflammation

“…Previous studies have shown that estrogen plays a role as an active substance leading to lipolysis and thereby offering protection against obesity development [ 36 , 37 ]. Thus, it is important to investigate whether estrogen deficiency is the primary factor in the development of hypothalamic inflammation revealed in the postmenopausal model or the alteration of metabolites associated with an expansion of fat tissues is also responsible for the same.…”