Selenoprotein S regulates adipogenesis through IRE1α-XBP1 pathway

in Journal of Endocrinology

Correspondence should be addressed to J Du or D Ren: or

*(L Men and J Yao contributed equally to this work)

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The induction of endoplasmic reticulum (ER) stress is associated with adipogenesis, during which the inositol-requiring enzyme 1 alpha (IRE1α)-X-box-binding protein 1 (XBP1) pathway is involved. Selenoprotein S (SelS), which is an ER resident selenoprotein, is involved in ER homeostasis regulation; however, little is known about the role of SelS in regulating adipogenesis. In vivo studies showed that SelS protein levels in white adipose tissue were increased in obese subjects and high-fat diet (HFD)-fed mice. Moreover, we identified that SelS protein levels increased in the early phase of adipogenesis and then decreased in the late phase during adipogenesis. Overexpression of SelS promoted adipogenesis. Conversely, knockdown (KD) of SelS resulted in the inhibition of adipogenesis, which was related to increasing cell death, decreased mitotic clonal expansion, and cell cycle G1 arrest. In vivo studies also showed that ER stress markers (p-IRE1α/IRE1α, XBP1s, and Grp78) were significantly increased with upregulating of SelS expression in subcutaneous and visceral adipose tissues in the obese subjects and HFD-fed mice. Furthermore, in SelS KD cells, the levels of Grp78 were increased and the levels of p-IRE1α/IRE1α were unchanged , but mRNA levels of spliced XBP1 (XBP1s) produced by IRE1α-mediated splicing were decreased, suggesting a role of SelS in the modulation of IRE1α-XBP1 pathway. Moreover, inhibition of adipogenesis by SelS suppression can be rescued by overexpression of XBP1s. Thus, SelS appears to function as a novel regulator of adipogenesis through the IRE1α-XBP1 signaling pathway.

Supplementary Materials

    • supplementary Figure 1 The body weight changes of mice feed with NC, 45% HFD and 60% HFD. Feeding of a 45% HFD and 60% HFD resulted in an increase in mice body weight. Values are means&#x00B1; SD (n = 6), *P < 0.05, **P < 0.01 , ***P < 0.001 versus NC.
    • supplementary Figure 2 The mRNA levels of SelS were performed by real-time quantitative PCR analysis during adipogenesis. The mRNA levels of SelS were increased from day 2 to day 8 compared with day 0. Values are means&#x00B1;SD (n = 3). * P < 0.05, ** P < 0.01 versus day0.
    • supplementary Figure 3 The mRNA levels of adipogenic markers (SREBP1, PPAR&#x03B3;, FASN, FABP4, C/EBP&#x03B1;, C/EBP&#x03B2;, Adipsin, Adiponectin) were performed by real-time quantitative PCR analysis in control and SelS KD 3T3-L1 cells on day 0, 2, 4, 6, and 8. Values are means&#x00B1;SD (n = 3). * P < 0.05, ** P < 0.01, *** P < 0.001 versus control.
    • Supplementary Table1 primary and secondary antibodies


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