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Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):12102-12111. doi: 10.1073/pnas.1814522115. Epub 2018 Nov 12.

PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice.

Author information

1
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390.
2
Touchstone Diabetes Center, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390.
3
Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390.
4
Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390.
5
Green Center for Reproductive Biology, UT Southwestern Medical Center, Dallas, TX 75390.
6
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390; davo.mango@utsouthwestern.edu steven.kliewer@utsouthwestern.edu.
7
Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390.
8
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390.

Abstract

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.

KEYWORDS:

PPARγ; SUMOylation; adipose tissue; insulin; rosiglitazone

PMID:
30420515
PMCID:
PMC6275522
DOI:
10.1073/pnas.1814522115
[Indexed for MEDLINE]
Free PMC Article

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