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Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice
OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J fem...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044006/ https://www.ncbi.nlm.nih.gov/pubmed/35364299 http://dx.doi.org/10.1016/j.molmet.2022.101482 |
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author | Stokar, Joshua Gurt, Irina Cohen-Kfir, Einav Yakubovsky, Oran Hallak, Noa Benyamini, Hadar Lishinsky, Natan Offir, Neta Tam, Joseph Dresner-Pollak, Rivka |
author_facet | Stokar, Joshua Gurt, Irina Cohen-Kfir, Einav Yakubovsky, Oran Hallak, Noa Benyamini, Hadar Lishinsky, Natan Offir, Neta Tam, Joseph Dresner-Pollak, Rivka |
author_sort | Stokar, Joshua |
collection | PubMed |
description | OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery. RESULTS: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = −0.7 p < 0.001) and liver triglyceride content (r = −0.4, p = 0.04), with a similar trend for serum adropin. In vitro, Enho expression was tripled by 17β-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16. CONCLUSIONS: OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement. |
format | Online Article Text |
id | pubmed-9044006 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-90440062022-04-28 Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice Stokar, Joshua Gurt, Irina Cohen-Kfir, Einav Yakubovsky, Oran Hallak, Noa Benyamini, Hadar Lishinsky, Natan Offir, Neta Tam, Joseph Dresner-Pollak, Rivka Mol Metab Original Article OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery. RESULTS: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = −0.7 p < 0.001) and liver triglyceride content (r = −0.4, p = 0.04), with a similar trend for serum adropin. In vitro, Enho expression was tripled by 17β-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16. CONCLUSIONS: OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement. Elsevier 2022-03-29 /pmc/articles/PMC9044006/ /pubmed/35364299 http://dx.doi.org/10.1016/j.molmet.2022.101482 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Stokar, Joshua Gurt, Irina Cohen-Kfir, Einav Yakubovsky, Oran Hallak, Noa Benyamini, Hadar Lishinsky, Natan Offir, Neta Tam, Joseph Dresner-Pollak, Rivka Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title | Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title_full | Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title_fullStr | Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title_full_unstemmed | Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title_short | Hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
title_sort | hepatic adropin is regulated by estrogen and contributes to adverse metabolic phenotypes in ovariectomized mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044006/ https://www.ncbi.nlm.nih.gov/pubmed/35364299 http://dx.doi.org/10.1016/j.molmet.2022.101482 |
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