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AOP: 497

Title

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ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome

Short name
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ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome
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Handbook Version v2.6

Graphical Representation

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Authors

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Min Ji Kim

Jean-Pascal De Bandt

Antoine Girardon

Etienne Blanc

Xavier Coumoul

Karine Audouze

Point of Contact

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Min Ji Kim   (email point of contact)

Contributors

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  • Min Ji Kim
  • Jean-Pascal de Bandt
  • Etienne Blanc
  • Xavier COUMOUL
  • Karine Audouze

Coaches

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OECD Information Table

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OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 09, 2024 16:52

Revision dates for related pages

Page Revision Date/Time
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, 2024 17:33
Increased, Oxidative Stress February 03, 2022 14:20
Impaired insulin signaling May 25, 2023 09:46
Metabolic syndrome May 25, 2023 09:51
N/A, Mitochondrial dysfunction 1 March 14, 2024 11:12
Insulin resistance, increased May 26, 2023 06:34
ERa inactivation leads to Decreased, Mitochondrial fatty acid beta-oxidation May 25, 2023 10:01
ERa inactivation leads to Increased, Reactive oxygen species May 25, 2023 10:03
Decreased, Mitochondrial fatty acid beta-oxidation leads to N/A, Mitochondrial dysfunction 1 March 13, 2024 17:25
Increased, Reactive oxygen species leads to Increased, Oxidative Stress July 31, 2023 15:55
N/A, Mitochondrial dysfunction 1 leads to Impaired insulin signaling March 13, 2024 17:26
Increased, Oxidative Stress leads to Impaired insulin signaling May 25, 2023 10:05
Impaired insulin signaling leads to Insulin resistance, increased April 09, 2024 16:51
Insulin resistance, increased leads to Metabolic syndrome April 09, 2024 16:51
Increased, Oxidative Stress leads to N/A, Mitochondrial dysfunction 1 March 13, 2024 17:25

Abstract

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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 [1]. In parallel, hormone replacement therapy has positive effects on insulin resistance [2]. 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 [3].

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 [4]. 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 [6]. 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 [7] 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

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
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Key Events (KE)
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Adverse Outcomes (AO)
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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 177 N/A, Mitochondrial dysfunction 1 N/A, Mitochondrial dysfunction 1
KE 1088 Increased, Oxidative Stress Increased, Oxidative Stress
KE 2144 Impaired insulin signaling Impaired insulin signaling
AO 2119 Insulin resistance, increased Insulin resistance, increased
AO 2145 Metabolic syndrome Metabolic syndrome

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help

[1]       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.

[2]       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.

[3]       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.

[4]       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.

[5]       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.

[6]       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.

[7]       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.