| First Author | Nguyen MT | Year | 2013 |
| Journal | Cell Death Differ | Volume | 20 |
| Issue | 12 | Pages | 1654-63 |
| PubMed ID | 24096869 | Mgi Jnum | J:228992 |
| Mgi Id | MGI:5749931 | Doi | 10.1038/cdd.2013.129 |
| Citation | Nguyen MT, et al. (2013) Hsp90 chaperones PPARgamma and regulates differentiation and survival of 3T3-L1 adipocytes. Cell Death Differ 20(12):1654-63 |
| abstractText | Adipose tissue dysregulation has a major role in various human diseases. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a key regulator of adipocyte differentiation and function, as well as a target of insulin-sensitizing drugs. The Hsp90 chaperone stabilizes a diverse set of signaling 'client' proteins, thereby regulates various biological processes. Here we report a novel role for Hsp90 in controlling PPARgamma stability and cellular differentiation. Specifically, we show that the Hsp90 inhibitors geldanamycin and novobiocin efficiently impede the differentiation of murine 3T3-L1 preadipocytes. Geldanamycin at higher concentrations also inhibits the survival of both developing and mature adipocytes, respectively. Further, Hsp90 inhibition disrupts an Hsp90-PPARgamma complex, leads to the destabilization and proteasomal degradation of PPARgamma, and inhibits the expression of PPARgamma target genes, identifying PPARgamma as an Hsp90 client. A similar destabilization of PPARgamma and a halt of adipogenesis also occur in response to protein denaturing stresses caused by a single transient heat-shock or proteasome inhibition. Recovery from stress restores PPARgamma stability and adipocyte differentiation. Thus, our findings reveal Hsp90 as a critical stress-responsive regulator of adipocyte biology and offer a potential therapeutic target in obesity and the metabolic syndrome. |
