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Training duplicate-Estrogen receptor alpha (ERa) inactivation alters mitochondrial functions and insulin signaling in skeletal muscle and leads to insulin resistance and metabolic syndrome
Point of Contact
- Arthur Author
- Min Ji Kim
- Jean-Pascal de Bandt
- Antoine Girardon
- Etienne Blanc
- Xavier COUMOUL
- Karine Audouze
- Travis Karschnik
|Handbook Version||OECD status||OECD project|
This AOP was last modified on June 07, 2023 08:51
|Estrogen receptor alpha inactivation||April 10, 2023 13:29|
|Decreased, Mitochondrial fatty acid beta-oxidation||September 16, 2017 10:14|
|Increased, Reactive oxygen species||April 10, 2023 14:01|
|Mitochondrial dysfunction||November 02, 2020 07:11|
|Increased, Oxidative Stress||February 03, 2022 14:20|
|Impaired insulin signaling||June 05, 2023 14:42|
|Insulin resistance||June 27, 2022 23:17|
|Metabolic syndrome||June 05, 2023 14:45|
|ERa inactivation leads to Increased, Reactive oxygen species||June 05, 2023 14:12|
|ERa inactivation leads to Decreased, Mitochondrial fatty acid beta-oxidation||June 05, 2023 14:14|
|Increased, Oxidative Stress leads to Mitochondrial dysfunction||June 05, 2023 14:47|
|Increased, Reactive oxygen species leads to Increased, Oxidative Stress||December 03, 2016 16:38|
|Decreased, Mitochondrial fatty acid beta-oxidation leads to Mitochondrial dysfunction||June 05, 2023 14:50|
|Mitochondrial dysfunction leads to Impaired insulin signaling||June 05, 2023 14:51|
|Increased, Oxidative Stress leads to Impaired insulin signaling||June 05, 2023 14:52|
|Impaired insulin signaling leads to Insulin resistance||June 05, 2023 14:53|
|Insulin resistance leads to Metabolic syndrome||June 05, 2023 14:55|
Estrogens are not only important in the development and functions of the reproductive system, but also play a role in metabolic functions and insulin sensitivity. Thus, before menopause, women display higher insulin sensitivity and lower propensity to develop metabolic dysfunction-related diseases such as insulin resistance, type 2 diabetes, cancers and cardiovascular diseases than men but, after menopause, incidence of these diseases is similar in both sex . In parallel, hormone replacement therapy has positive effects on insulin resistance . Similarly, men with a mutation in the aromatase gene, who don’t have circulating estrogen, develop insulin resistance that can be reversed by estrogen therapy .
Skeletal muscle is known to play a central role in the development of insulin resistance (IR). Due to the important mass of skeletal muscle (30 to 40% of total body mass), any defect in glucose entry into the muscle cells, caused by muscle IR, significantly affects whole body glucose disposition. Subsequently, IR in skeletal muscle favors hyperglycemia and increase the risk of type 2 diabetes . The importance of estrogens and their effects mediated through ERa in insulin resistance was suggested by whole body ERa knock-out (KO) and muscle-specific ERa KO mice that are obese and insulin resistant [5,6]. A negative association between muscle ERa expression and fat mass or insulinemia is observed in women and in genetically obese mice emphasizing the importance of muscle ERa signaling in insulin sensitivity . Thus, the alterations resulting from reduced muscle ERa activity is important to consider to better understand mechanisms leading to muscle insulin resistance.
Decreased mitochondrial oxidative capacity, increased production of reactive oxygen species and impaired insulin signaling should be considered as they are known to be key features of insulin-resistant muscle  and are also present in ERa KO mice [5,6].
Thus, the AOP that we propose here links the inactivation of ERa in skeletal muscle to one of the hallmarks of the metabolic syndrome that is insulin resistance taking account the following events “decreased mitochondrial fatty acid oxidation”, “increased reactive oxygen species”, “mitochondrial dysfunction”, “increased oxidative stress” and “impaired insulin signaling”.
AOP Development Strategy
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||2126||Estrogen receptor alpha inactivation||ERa inactivation|
|KE||179||Decreased, Mitochondrial fatty acid beta-oxidation||Decreased, Mitochondrial fatty acid beta-oxidation|
|KE||1115||Increased, Reactive oxygen species||Increased, Reactive oxygen species|
|KE||1816||Mitochondrial dysfunction||Mitochondrial dysfunction|
|KE||1088||Increased, Oxidative Stress||Increased, Oxidative Stress|
|KE||2134||Impaired insulin signaling||Impaired insulin signaling|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
Considerations for Potential Applications of the AOP (optional)
 M.C. Carr, The emergence of the metabolic syndrome with menopause, J Clin Endocrinol Metab. 88 (2003) 2404–2411. https://doi.org/10.1210/jc.2003-030242.
 F. Mauvais-Jarvis, J.E. Manson, J.C. Stevenson, V.A. Fonseca, Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications, Endocr Rev. 38 (2017) 173–188. https://doi.org/10.1210/er.2016-1146.
 V. Rochira, B. Madeo, L. Zirilli, G. Caffagni, L. Maffei, C. Carani, Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men, Diabet Med. 24 (2007) 1491–1495. https://doi.org/10.1111/j.1464-5491.2007.02304.x.
 R.A. DeFronzo, D. Tripathy, Skeletal muscle insulin resistance is the primary defect in type 2 diabetes, Diabetes Care. 32 Suppl 2 (2009) S157-163. https://doi.org/10.2337/dc09-S302.
 V. Ribas, M.T.A. Nguyen, D.C. Henstridge, A.-K. Nguyen, S.W. Beaven, M.J. Watt, A.L. Hevener, Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice, Am J Physiol Endocrinol Metab. 298 (2010) E304-319. https://doi.org/10.1152/ajpendo.00504.2009.
 V. Ribas, B.G. Drew, Z. Zhou, J. Phun, N.Y. Kalajian, T. Soleymani, P. Daraei, K. Widjaja, J. Wanagat, T.Q. de Aguiar Vallim, A.H. Fluitt, S. Bensinger, T. Le, C. Radu, J.P. Whitelegge, S.W. Beaven, P. Tontonoz, A.J. Lusis, B.W. Parks, L. Vergnes, K. Reue, H. Singh, J.C. Bopassa, L. Toro, E. Stefani, M.J. Watt, S. Schenk, T. Akerstrom, M. Kelly, B.K. Pedersen, S.C. Hewitt, K.S. Korach, A.L. Hevener, Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, Sci Transl Med. 8 (2016) 334ra54. https://doi.org/10.1126/scitranslmed.aad3815.
 S. Di Meo, S. Iossa, P. Venditti, Skeletal muscle insulin resistance: role of mitochondria and other ROS sources, J Endocrinol. 233 (2017) R15–R42. https://doi.org/10.1530/JOE-16-0598.