Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest)
Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated wit...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481029/ https://www.ncbi.nlm.nih.gov/pubmed/28640866 http://dx.doi.org/10.1371/journal.pone.0179879 |
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author | Anunciado-Koza, Rea P. Manuel, Justin Mynatt, Randall L. Zhang, Jingying Kozak, Leslie P. Koza, Robert A. |
author_facet | Anunciado-Koza, Rea P. Manuel, Justin Mynatt, Randall L. Zhang, Jingying Kozak, Leslie P. Koza, Robert A. |
author_sort | Anunciado-Koza, Rea P. |
collection | PubMed |
description | Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (Mest(gKO)) and paternal allelic (Mest(pKO)) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335. Mest(pKO) mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of Mest were phenotypically similar to Mest(pKO), supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and Mest(pKO) mice detected few differences between genotypes; nevertheless, genes with reduced expression in Mest(pKO) mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from Mest(gKO) mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of Gpat4, an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from Mest(gKO) after Gpat4 knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet-induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of Mest in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes. |
format | Online Article Text |
id | pubmed-5481029 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54810292017-07-05 Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) Anunciado-Koza, Rea P. Manuel, Justin Mynatt, Randall L. Zhang, Jingying Kozak, Leslie P. Koza, Robert A. PLoS One Research Article Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (Mest(gKO)) and paternal allelic (Mest(pKO)) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335. Mest(pKO) mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of Mest were phenotypically similar to Mest(pKO), supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and Mest(pKO) mice detected few differences between genotypes; nevertheless, genes with reduced expression in Mest(pKO) mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from Mest(gKO) mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of Gpat4, an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from Mest(gKO) after Gpat4 knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet-induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of Mest in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes. Public Library of Science 2017-06-22 /pmc/articles/PMC5481029/ /pubmed/28640866 http://dx.doi.org/10.1371/journal.pone.0179879 Text en © 2017 Anunciado-Koza et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Anunciado-Koza, Rea P. Manuel, Justin Mynatt, Randall L. Zhang, Jingying Kozak, Leslie P. Koza, Robert A. Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title | Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title_full | Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title_fullStr | Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title_full_unstemmed | Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title_short | Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest) |
title_sort | diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (mest) |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481029/ https://www.ncbi.nlm.nih.gov/pubmed/28640866 http://dx.doi.org/10.1371/journal.pone.0179879 |
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