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Endocrine Abstracts (2013) 31 P201 | DOI: 10.1530/endoabs.31.P201

Warwick Medical School, University of Warwick, Coventry, UK.

Background: Adipose tissue (AT) plays a central role in obesity-related complications such as cardiovascular diseases, insulin resistance, and type two diabetes. A comprehensive understanding of the molecular mechanisms underlying adipocyte formation is of both fundamental and clinical relevance. It has been reported that UPR pathway, IRE1α-XBP1 regulates hepatic lipogenesis and the role of this pathway in adipogenesis in murine adipocytes has also been confirmed. Our team has also shown that this pathway is upregulated in obese human AT. Therefore, we further investigated the role of IRE1α-XBP1 pathway in the process of adipogenesis in lean and obese human preadipocytes.

Methods: A human preadipocyte cell line Chub-S7 (n=3) and abdominal subcutaneous (AbdSc) preadipocytes (Ad) from lean (n=3, BMI: 22.47(±S.D. 2.55) kg/m2, age: 35.3(±S.D. 8.50) years) and obese (n=3, BMI: 31.97 (±S.D. 1.26) kg/m2, age: 31.0 (±S.D. 7.55) years) individuals were differentiated over 14 days and markers of adipogenesis and IRE1α, XBP1 and spliced XBP1 (XBP1s) were assessed using qRT-PCR and western blotting.

Results: In Chub-S7 adipocytes IRE1α mRNA expression oscillated through differentiation peaking at days 4 and 12, with an eight- and sixfold increased expression relative to day 0, respectively (P<0.01, P<0.01). A similar pattern of mRNA expression of IRE1α during differentiation of all AbdSc Ad was observed. XBP1s mRNA expression in Chub-S7 cells peaked on day 4 only (90-fold expression relative to day 0; P<0.01). XBP1s mRNA expression in obese AbdSc Ad matched that of IRE1α with a 12-fold peak rise on days 4 and 12, whilst in AbdSc Ad from lean subjects XBP1s remained unchanged.

Conclusions: i) The IRE1α-XBP1 pathway is induced during adipogenesis in an oscillatory manner and may have an important role in this process. ii) IRE1α and XBP1s expression was enhanced during differentiation of obese AbdSc Ad compared to lean. These data highlight with weight gain subtle changes in UPR pathway, IRE1α-XBP1 may lead to downstream metabolic consequences.

Declaration of funding: This work was supported by the Biotechnology and Biological Sciences Research Council, Birmingham Science City and AstraZeneca.

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