Cargando…
Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge
BACKGROUND: The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466809/ https://www.ncbi.nlm.nih.gov/pubmed/30987673 http://dx.doi.org/10.1186/s13293-019-0233-y |
_version_ | 1783411181127467008 |
---|---|
author | Ghosh, Sujoy Taylor, Jessica L. Mendoza, Tamra M. Dang, Thanh Burk, David H. Yu, Yongmei Kilroy, Gail Floyd, Z. Elizabeth |
author_facet | Ghosh, Sujoy Taylor, Jessica L. Mendoza, Tamra M. Dang, Thanh Burk, David H. Yu, Yongmei Kilroy, Gail Floyd, Z. Elizabeth |
author_sort | Ghosh, Sujoy |
collection | PubMed |
description | BACKGROUND: The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age. METHODS: Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA. RESULTS: Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels. CONCLUSIONS: The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13293-019-0233-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6466809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64668092019-04-22 Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge Ghosh, Sujoy Taylor, Jessica L. Mendoza, Tamra M. Dang, Thanh Burk, David H. Yu, Yongmei Kilroy, Gail Floyd, Z. Elizabeth Biol Sex Differ Research BACKGROUND: The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age. METHODS: Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA. RESULTS: Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels. CONCLUSIONS: The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13293-019-0233-y) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-15 /pmc/articles/PMC6466809/ /pubmed/30987673 http://dx.doi.org/10.1186/s13293-019-0233-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ghosh, Sujoy Taylor, Jessica L. Mendoza, Tamra M. Dang, Thanh Burk, David H. Yu, Yongmei Kilroy, Gail Floyd, Z. Elizabeth Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title | Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title_full | Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title_fullStr | Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title_full_unstemmed | Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title_short | Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
title_sort | siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466809/ https://www.ncbi.nlm.nih.gov/pubmed/30987673 http://dx.doi.org/10.1186/s13293-019-0233-y |
work_keys_str_mv | AT ghoshsujoy siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT taylorjessical siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT mendozatamram siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT dangthanh siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT burkdavidh siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT yuyongmei siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT kilroygail siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge AT floydzelizabeth siah2modulatessexdependentmetabolicandinflammatoryresponsesinadiposetissuetoahighfatdietchallenge |