X-box binding protein 1 is a novel key regulator of peroxisome proliferator-activated receptor γ2.

Abstract

X-box binding protein 1 (XBP1), a transcription factor of the unfolded protein

response, plays various roles in many biological processes. We examined its

pro-adipogenic activity and target genes during adipogenic differentiation in

wild-type and genetically modified 3T3-L1 cells. Signalling pathways that

contribute to Xbp1 mRNA splicing, and the correlation of the transcriptionally

active XBP1 isoform (XBP1s) level with body mass index and the level of

peroxisome proliferator-activated receptor gamma2 (PPARgamma2) in human adipose

tissues were also examined. The mRNA and nuclear protein expression levels of

XBP1s increased immediately following hormonal induction of adipogenesis,

reaching a peak at 6 h. Results from cDNA microarray and gene expression analyses

using genetically modified cells indicated that PPARgamma2 was a principal target

of XBP1s. The XBP1s-specific binding motif, which is distinct from the

CCAAT/enhancer-binding protein alpha binding site, was identified in the

PPARgamma2 promoter by site-directed mutagenesis. Fetal bovine serum, insulin,

3-isobutyl-1-methylxanthine and dexamethasone contributed independently to Xbp1

mRNA splicing. In human subcutaneous adipose tissues, the levels of both Xbp1s

and Ppargamma2 mRNA increased proportionally with body mass index, and there was

a significant positive correlation between the two genes. These data suggest for

the first time that positive regulation of PPARgamma2 is a principal mechanism of

XBP1s-mediated adipogenesis in 3T3-L1 cells.