| First Author | Katafuchi T | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 48 | Pages | 12102-12111 |
| PubMed ID | 30420515 | Mgi Jnum | J:269302 |
| Mgi Id | MGI:6259518 | Doi | 10.1073/pnas.1814522115 |
| Citation | Katafuchi T, et al. (2018) PPARgamma-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice. Proc Natl Acad Sci U S A 115(48):12102-12111 |
| abstractText | The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma 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 PPARgamma is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARgamma-K107R-mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARgamma activation by TZDs. Accordingly, the PPARgamma-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 PPARgamma SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARgamma's beneficial insulin-sensitizing effect from its adverse effect of weight gain. |
