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AOP: 496

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Training duplicate-Estrogen receptor alpha (ERa) inactivation alters mitochondrial functions and insulin signaling 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

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Point of Contact

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Arthur Author   (email point of contact)

Contributors

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  • Arthur Author
  • Min Ji Kim
  • Jean-Pascal de Bandt
  • Antoine Girardon
  • Etienne Blanc
  • Xavier COUMOUL
  • Karine Audouze

Coaches

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  • Travis Karschnik

Status

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Handbook Version OECD status OECD project
v2.5
This AOP was last modified on June 07, 2023 08:51

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, 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

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)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
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
AO 2018 Insulin resistance Insulin resistance
AO 2135 Metabolic syndrome Metabolic syndrome

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
ERa inactivation leads to Increased, Reactive oxygen species adjacent High
ERa inactivation leads to Decreased, Mitochondrial fatty acid beta-oxidation adjacent High
Increased, Oxidative Stress leads to Mitochondrial dysfunction adjacent High
Increased, Reactive oxygen species leads to Increased, Oxidative Stress adjacent High
Decreased, Mitochondrial fatty acid beta-oxidation leads to Mitochondrial dysfunction adjacent High
Mitochondrial dysfunction leads to Impaired insulin signaling adjacent Moderate
Increased, Oxidative Stress leads to Impaired insulin signaling adjacent High
Impaired insulin signaling leads to Insulin resistance adjacent High
Insulin resistance leads to Metabolic syndrome adjacent High

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.