Cargando…
PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice
The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPAR...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275522/ https://www.ncbi.nlm.nih.gov/pubmed/30420515 http://dx.doi.org/10.1073/pnas.1814522115 |
_version_ | 1783377823180783616 |
---|---|
author | Katafuchi, Takeshi Holland, William L. Kollipara, Rahul K. Kittler, Ralf Mangelsdorf, David J. Kliewer, Steven A. |
author_facet | Katafuchi, Takeshi Holland, William L. Kollipara, Rahul K. Kittler, Ralf Mangelsdorf, David J. Kliewer, Steven A. |
author_sort | Katafuchi, Takeshi |
collection | PubMed |
description | The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain. |
format | Online Article Text |
id | pubmed-6275522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-62755222018-12-05 PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice Katafuchi, Takeshi Holland, William L. Kollipara, Rahul K. Kittler, Ralf Mangelsdorf, David J. Kliewer, Steven A. Proc Natl Acad Sci U S A Biological Sciences The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain. National Academy of Sciences 2018-11-27 2018-11-12 /pmc/articles/PMC6275522/ /pubmed/30420515 http://dx.doi.org/10.1073/pnas.1814522115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Katafuchi, Takeshi Holland, William L. Kollipara, Rahul K. Kittler, Ralf Mangelsdorf, David J. Kliewer, Steven A. PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title | PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title_full | PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title_fullStr | PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title_full_unstemmed | PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title_short | PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice |
title_sort | pparγ-k107 sumoylation regulates insulin sensitivity but not adiposity in mice |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275522/ https://www.ncbi.nlm.nih.gov/pubmed/30420515 http://dx.doi.org/10.1073/pnas.1814522115 |
work_keys_str_mv | AT katafuchitakeshi ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice AT hollandwilliaml ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice AT kollipararahulk ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice AT kittlerralf ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice AT mangelsdorfdavidj ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice AT kliewerstevena ppargk107sumoylationregulatesinsulinsensitivitybutnotadiposityinmice |