Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes

• Published in: Cell death and differentiation Vol. 20; no. 12; pp. 1654 - 1663
• Main Authors: Nguyen, M T, Csermely, P, Sőti, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 3T3-L1 Cells; 631/136/142; 631/443/319/1642; 631/45/612/1241; 692/698/690/2816; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis - drug effects; Adipogenesis - genetics; Animals; Apoptosis; Benzoquinones - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Survival - drug effects; Cell Survival - genetics; Hep G2 Cells; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic - pharmacology; Life Sciences; Mice; Original Paper; PPAR gamma - genetics; PPAR gamma - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Binding - drug effects; Protein Folding - drug effects; Protein Stability - drug effects; Proteolysis - drug effects; Stem Cells; Stress, Physiological - drug effects; Stress, Physiological - genetics; Transcription, Genetic - drug effects; stress; adipogenesis; proteostasis; diabetes; obesity
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.129

Adipose tissue dysregulation has a major role in various human diseases. The peroxisome proliferator-activated receptor- γ (PPAR γ ) 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 PPAR γ 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-PPAR γ complex, leads to the destabilization and proteasomal degradation of PPAR γ , and inhibits the expression of PPAR γ target genes, identifying PPAR γ as an Hsp90 client. A similar destabilization of PPAR γ 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 PPAR γ 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.