GPER and ERĪ± mediate estradiol enhancement of mitochondrial function in inflamed adipocytes through a PKA dependent mechanism.
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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 (ERĪ±, ERĪ² 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 ERĪ±, ERĪ², and GPER signaling to the E2-mediated enhancement of adipocyte mitochondrial function in a pro-inflammatory situation. 3T3-L1 cells were treated for 24āh 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 ERĪ± and GPER, but not ERĪ², 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 ERĪ±. These findings expand our understanding of ER interactions under inflammatory conditions in female rodent white adipose tissue.
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1879-1220
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MRC (Unknown)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_UU_12012/2)
Biotechnology and Biological Sciences Research Council (BB/J009865/1)
British Heart Foundation (None)
MRC (MC_UU_00014/2)
Medical Research Council (MC_PC_12012)