Role of the High Molegular Weight Immunophilin FKBP51 during adipocyte differentiation

GUBER S, GALIGNIANA MD, PIWIEN PILIPUK G

SEEON, ALEMANIA

Congreso; 4th International Conference on the Hsp90 Chaperone Machinery; 2008

Obesity is the resultant of both increased adipocyte size and development of new fat cells. Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR), which exists as an oligomer bound to hsp90 and high MW immunophilins (IMMs). Here, we studied the role of IMMs in adipogenesis. When adipogenesis was induced with a cocktail containing dexamethasone, IBMX and insulin, FKBP51 expression progressively increased whereas FKBP52 faded. Hsp90, hsp70 and Cyp40 remained unchanged. Interestingly, FKBP51 translocated to the nucleus co-localizing with GR. FKBP51 nuclear localization was transient, 48 h after the induction it cycled back to mitochondria. Co-immunoprecipitation assays showed that GR is complexed with more FKBP51 than FKBP52 during the induction. Reporter gene assays showed that FKBP51 reduced GR transcriptional capacity, suggesting that nuclear FKBP51 controls GR target genes during the differentiation. IBMX alone promoted an efficient nuclear relocalization of FKBP51. Since increased cAMP leads to PKA activation, we assayed the effect of PKI and found that FKBP51 relocalization was abrogated. PKA signaling is required for 3T3-L1 cells to differentiate in adipocytes, CREB being a well known PKA target. When adipogenesis was induced, phospho-CREB co-localized with nuclear FKBP51. Immunoprecipitation assays showed that FKBP51 interacts with CREB. Importantly, overexpression of FKP51 increased CREB-dependent c-fos promoter activity. In summary, FKBP51 shows dynamic changes of expression and concentrates in the nucleus at the onset of adipocyte differentiation in response to PKA signaling cascade. This transient nuclear concentration may play a key role in the control of the expression of genes required to acquire the adipocyte phenotype.