期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 48, 页码 12102-12111出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1814522115
关键词
PPAR gamma; SUMOylation; adipose tissue; insulin; rosiglitazone
资金
- NIH [R01DK108833, R01DK112826, R01DK067158, P01AG051459]
- Robert A. Welch Foundation [I-1558, I-1275]
- Howard Hughes Medical Institute
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK067158, R01DK112826, R01DK108833] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG051459] Funding Source: NIH RePORTER
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 gamma 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 PPAR gamma is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPAR gamma-K107R-mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPAR gamma activation by TZDs. Accordingly, the PPAR gamma-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 PPAR gamma SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPAR gamma's beneficial insulin-sensitizing effect from its adverse effect of weight gain.
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