GPER and ERα mediate estradiol enhancement of mitochondrial function in inflamed adipocytes through a PKA dependent mechanism

J Steroid Biochem Mol Biol. 2019 Jan;185:256-267. doi: 10.1016/j.jsbmb.2018.09.013. Epub 2018 Sep 22.


Obesity is associated with inflammation, dysregulated adipokine secretion, and disrupted adipose tissue mitochondrial function. Estradiol (E2) has been previously reported to increase mitochondrial function and biogenesis in several cell lines, but neither the type of oestrogen receptor (ERα, ERβ and GPER) involved nor the mechanism whereby such effects are exerted have been fully described. Considering the anti-inflammatory activity of E2 as well as its effects in enhancing mitochondrial biogenesis, the aim of this study was to investigate the contribution of ERα, ERβ, and GPER signaling to the E2-mediated enhancement of adipocyte mitochondrial function in a pro-inflammatory situation. 3T3-L1 cells were treated for 24 h with ER agonists (PPT, DPN, and G1) and antagonists (MPP, PHTPP, and G15) in the presence or absence of interleukin 6 (IL6), as a pro-inflammatory stimulus. Inflammation, mitochondrial function and biogenesis markers were analyzed. To confirm the involvement of the PKA pathway, cells were treated with a GPER agonist, a PKA inhibitor, and IL6. Mitochondrial function markers were analyzed. Our results showed that activation of ERα and GPER, but not ERβ, was able to counteract the proinflammatory effects of IL6 treatment, as well as mitochondrial biogenesis and function indicators. Inhibition of PKA prevented the E2- and G1-associated increase in mitochondrial function markers. In conclusion E2 prevents IL6 induced inflammation in adipocytes and promotes mitochondrial function through the combined activation of both GPER and ERα. These findings expand our understanding of ER interactions under inflammatory conditions in female rodent white adipose tissue.

Keywords: 17beta-estradiol; G protein-coupled oestrogen receptor adipocyte; Mitochondrial function; Oestrogen receptor alpha; PKA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adipocytes / pathology*
  • Animals
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / metabolism
  • Female
  • Inflammation / pathology
  • Interleukin-6 / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Obesity / pathology
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Interleukin-6
  • Receptors, G-Protein-Coupled
  • interleukin-6, mouse
  • Estradiol
  • Cyclic AMP-Dependent Protein Kinases