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The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.

AOP: 493

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

ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesity

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
ERa inactivation leads to increased fat mass and insulin resistance.
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Min Ji Kim1, Etienne Blanc2, Jean Pascal De Bandt2, Antoine Girardon2, Xavier Coumoul2, Karine Audouze2

1. Université Sorbonne Paris Nord, Inserm 1124, Paris, France

2. Université Paris Cité, Inserm 1124, Paris, France

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Min Ji Kim   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Min Ji Kim
  • Xavier COUMOUL
  • Karine Audouze
  • Jean-Pascal de Bandt
  • Etienne Blanc
  • Antoine Girardon

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 09, 2024 16:42

Revision dates for related pages

Page Revision Date/Time
Increased, recruitment of inflammatory cells May 12, 2023 17:03
Increased adipocyte size April 05, 2023 05:50
Increased adipocyte numbers April 05, 2023 05:51
Metabolically unhealthy Obesity April 05, 2023 05:55
Increased fat mass April 05, 2023 05:34
Estrogen receptor alpha inactivation April 10, 2023 13:29
increased lipid accumulation April 05, 2023 07:06
Increased pro-inflammatory cytokine expression April 06, 2023 10:15
Increase in inflammation May 03, 2019 14:27
Insulin resistance, increased May 26, 2023 06:34
ERa inactivation leads to Increased adipocyte numbers April 06, 2023 10:20
Increased adipocyte numbers leads to Increased fat mass May 04, 2023 05:48
Increased adipocyte size leads to Increased fat mass May 04, 2023 05:48
increased lipid accumulation leads to Increased fat mass May 04, 2023 05:49
Increased fat mass leads to Increased cytokine expression May 04, 2023 05:49
Increased fat mass leads to Recruitment of inflammatory cells April 05, 2023 05:38
ERa inactivation leads to increased lipid accumulation May 04, 2023 05:57
ERa inactivation leads to Increased adipocyte size April 06, 2023 10:18
Recruitment of inflammatory cells leads to Increase in inflammation May 04, 2023 05:51
Increased cytokine expression leads to Increase in inflammation May 04, 2023 05:51
Increase in inflammation leads to Insulin resistance, increased April 09, 2024 16:40
Insulin resistance, increased leads to Metabolically unhealthy Obesity April 09, 2024 16:40

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Estrogens are not only important in the development and the functions of reproductive system, but they also play a crucial role in adipose tissue distribution and insulin sensitivity and these effects mainly seem to be mediated by one of their receptors, ERa (estrogen receptor alpha). Indeed, ERa KO, but not ERb KO mice show an increased fat mass and insulin resistance phenotype in both sexes [1–3]. ERa deletion also leads to adipose tissue inflammation with an increased expression of pro-inflammatory cytokines and impaired insulin signaling in adipose tissue leading to insulin resistance [3]. An increased adiposity, an increased inflammation and an increased risk of obesity-related metabolic disorders such as insulin resistance, type 2 diabetes and cardiovascular disease can also be encountered in ovariectomized female mice or in postmenopausal women and weight gain or metabolic disorders are improved by E2 treatment or hormone therapy [4–7]. Furthermore, higher insulin resistance and/or adiposity were observed in men [8] and in postmenopausal women treated with aromatase inhibitors [9]. Aromatase-deficient mice, a model of estrogen insufficiency, also display an increased adiposity that is reversed by estrogen replacement [10].

An increased fat mass, inflammation and insulin resistance are hallmarks of the metabolic syndrome but there is no AOP considering the “increased adipocyte numbers” or “size” or “increased lipid accumulation” that lead to the “increased fat mass”. Furthermore, if the “recruitment of inflammatory cells” is an existing KE (1497) in AOP wiki, “increased pro-inflammatory cytokine expression”, that is commonly measured in experimental laboratories is missing. These events are well-known factor linking obesity and insulin resistance (KE 2119) leading to metabolically unhealthy obesity [11,12].

Thus, we propose an AOP linking ESR1 inactivation to the hallmarks of the metabolic syndrome because impairment of estrogen synthesis and of ERa signaling that can lead to the events must be considered to decipher mechanisms of action leading to the metabolic syndrome.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

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 1497 Increased, recruitment of inflammatory cells Recruitment of inflammatory cells
KE 2119 Insulin resistance, increased Insulin resistance, increased
KE 2127 Increased adipocyte size Increased adipocyte size
KE 2128 Increased adipocyte numbers Increased adipocyte numbers
KE 2125 Increased fat mass Increased fat mass
KE 2130 increased lipid accumulation increased lipid accumulation
KE 2132 Increased pro-inflammatory cytokine expression Increased cytokine expression
KE 1633 Increase in inflammation Increase in inflammation
AO 2129 Metabolically unhealthy Obesity Metabolically unhealthy Obesity

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
ERa inactivation leads to Increased adipocyte numbers adjacent High
Increased adipocyte numbers leads to Increased fat mass adjacent High
Increased adipocyte size leads to Increased fat mass adjacent High
increased lipid accumulation leads to Increased fat mass adjacent High
Increased fat mass leads to Increased cytokine expression adjacent High
Increased fat mass leads to Recruitment of inflammatory cells adjacent High
ERa inactivation leads to increased lipid accumulation adjacent High
ERa inactivation leads to Increased adipocyte size adjacent High
Recruitment of inflammatory cells leads to Increase in inflammation adjacent High
Increased cytokine expression leads to Increase in inflammation adjacent High
Increase in inflammation leads to Insulin resistance, increased adjacent High
Insulin resistance, increased leads to Metabolically unhealthy Obesity adjacent High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Mus musculus Mus musculus High NCBI
Homo sapiens Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female High
Male High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

[1]       P.A. Heine, J.A. Taylor, G.A. Iwamoto, D.B. Lubahn, P.S. Cooke, Increased adipose tissue in male and female estrogen receptor-alpha knockout mice, Proc Natl Acad Sci U S A. 97 (2000) 12729–12734. https://doi.org/10.1073/pnas.97.23.12729.

[2]       C. Ohlsson, N. Hellberg, P. Parini, O. Vidal, M. Bohlooly-Y, M. Rudling, M.K. Lindberg, M. Warner, B. Angelin, J.A. Gustafsson, Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice, Biochem Biophys Res Commun. 278 (2000) 640–645. https://doi.org/10.1006/bbrc.2000.3827.

[3]       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.

[4]       N. Geary, L. Asarian, K.S. Korach, D.W. Pfaff, S. Ogawa, Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice, Endocrinology. 142 (2001) 4751–4757. https://doi.org/10.1210/endo.142.11.8504.

[5]       L.B. Jensen, P. Vestergaard, A.P. Hermann, J. Gram, P. Eiken, B. Abrahamsen, C. Brot, N. Kolthoff, O.H. Sørensen, H. Beck-Nielsen, S.P. Nielsen, P. Charles, L. Mosekilde, Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study, J Bone Miner Res. 18 (2003) 333–342. https://doi.org/10.1359/jbmr.2003.18.2.333.

[6]       K.L. Margolis, D.E. Bonds, R.J. Rodabough, L. Tinker, L.S. Phillips, C. Allen, T. Bassford, G. Burke, J. Torrens, B.V. Howard, Women’s Health Initiative Investigators, Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial, Diabetologia. 47 (2004) 1175–1187. https://doi.org/10.1007/s00125-004-1448-x.

[7]       N.H. Rogers, J.W. Perfield, K.J. Strissel, M.S. Obin, A.S. Greenberg, Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity, Endocrinology. 150 (2009) 2161–2168. https://doi.org/10.1210/en.2008-1405.

[8]       F.W. Gibb, N.Z.M. Homer, A.M.M. Faqehi, R. Upreti, D.E. Livingstone, K.J. McInnes, R. Andrew, B.R. Walker, Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men, J Clin Endocrinol Metab. 101 (2016) 2040–2046. https://doi.org/10.1210/jc.2015-4146.

[9]       F.W. Gibb, J.M. Dixon, C. Clarke, N.Z. Homer, A.M.M. Faqehi, R. Andrew, B.R. Walker, Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors, J Clin Endocrinol Metab. 104 (2019) 3670–3678. https://doi.org/10.1210/jc.2018-02339.

[10]     M.E. Jones, A.W. Thorburn, K.L. Britt, K.N. Hewitt, N.G. Wreford, J. Proietto, O.K. Oz, B.J. Leury, K.M. Robertson, S. Yao, E.R. Simpson, Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity, Proc Natl Acad Sci U S A. 97 (2000) 12735–12740. https://doi.org/10.1073/pnas.97.23.12735.

[11]     M. Longo, F. Zatterale, J. Naderi, L. Parrillo, P. Formisano, G.A. Raciti, F. Beguinot, C. Miele, Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications, Int J Mol Sci. 20 (2019) 2358. https://doi.org/10.3390/ijms20092358.

[12]     A.R. Saltiel, J.M. Olefsky, Inflammatory mechanisms linking obesity and metabolic disease, J Clin Invest. 127 (2017) 1–4. https://doi.org/10.1172/JCI92035.