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 γ2 (PPARγ2) 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 PPARγ2 was a principal target of XBP1s. The XBP1s‐specific binding motif, which is distinct from the CCAAT/enhancer‐binding protein α binding site, was identified in the PPARγ2 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 Pparγ2 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 PPARγ2 is a principal mechanism of XBP1s‐mediated adipogenesis in 3T3‐L1 cells.

miR-148a is a downstream effector of X-box-binding protein 1 that silences Wnt10b during adipogenesis of 3T3-L1 cells

“…As we previously reported, the level of XBP1 mRNA was increased in two phases: a strong peak at ~6 h and a less potent peak on day 6 after the induction. 13 miR-148a expression, consistent with previous reports, was not increased within 24 h, but it began to increase at 6 days after adipogenic induction ( Supplementary Figure S1 ). 7 , 26 In the same context, the cAMP-response element-binding protein (CREB), which is known to regulate adipogenesis during the very early period, has been recently suggested as a putative upstream regulator of miR-148a.…”

“…Therefore, it is plausible that in addition to directly suppressing Wnt10b transcription during the early phase of adipogenesis, XBP1s may intensify adipogenic differentiation by inducing miR-148a, which, in turn, can disinhibit Wnt10b-mediated suppression of PPARγ2 during the late phase of adipogenesis. Moreover, considering that important pro- and anti-adipogenic molecules such as PPARγ2, 13 Wnt10b 16 and C/EBPα 14 are regulated by XBP1s, our data identifying miR-148a as an additional target molecule for XBP1s strongly support the idea that XBP1 plays a critical role in adipogenesis through multiple mechanisms ( Figure 5 ).…”

“… 12 Many reports have recently demonstrated the involvement of XBP1 in the regulation of adipogenesis. 13 , 14 , 15 We have also reported that XBP1s has a pro-adipogenic role by transcriptional regulation of peroxisome proliferator-activated receptor γ (PPARγ) 13 and Wnt10b. 16 For the latter, XBP1 induces adipogenesis by directly suppressing Wnt10b transcription, and, recently, we found that Wnt10b mRNA stability could be decreased by XBP1s.…”

EMC3 coordinates surfactant protein and lipid homeostasis required for respiration

“…During ER stress, activated UPR can interfere with SREBP signaling and thus disrupt lipid metabolism. PPARγ and PPARα, transcriptional targets of XBP1 (28)(29)(30), may induce expression of Insig-1/2, thus reducing levels of active SREBP (31,32). Likewise, ISR activation following eIF2α phosphorylation reduced active SREBP and the transcription of target genes involved in lipid synthesis (33), providing potential mechanisms by which SREBP signaling is inhibited in the absence of Emc3.…”

Tubby-like protein superfamily member PLSCR3 functions as a negative regulator of adipogenesis in mouse 3T3-L1 preadipocytes by suppressing induction of late differentiation stage transcription factors

“…Overexpression of hScr3 suppressed induction of late differentiation stage pro-adipogenic transcription factors (C/EBPα and PPARγ) but not early stage pro-adipogenic transcription factors (C/EBPβ and C/EBPδ) ( Figure 5 ). Expression of C/EBPα and PPARγ is induced by mutual transacting activities of C/EBPα and PPARγ and by upstream activators including C/EBPβ, C/EBPδ and ER stress-activated spliced XBP1 (sXBP1) [ 34 , 43 , 51 ]. The mRNA of XBP1 including the cytoplasmically-unspliced inactive form is induced by C/EBPβ and ER stress-response ATF6 as well by sXBP1 as self-induction [ 34 , 52 , 53 ].…”