Hsp90 chaperones PPAR? and regulates differentiation and survival of 3T3-L1 adipocytes.

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

SUBMITTER: Nguyen MT 

PROVIDER: S-EPMC3824595 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature