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Papers In Press, published online ahead of print December 1, 2009
J. Lipid Res., doi:10.1194/jlr.M900216-JLR200

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Journal of Lipid Research, Vol. 50, 2486-2501, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response^[S]

Sana Basseri^*, árka Lhoták^*, Arya M. Sharma and Richard C. Austin^1,*

^* Department of Medicine, McMaster University, St. Joseph's Healthcare Hamilton and the Henderson Research Centre, Hamilton, Ontario, L8N 4A6, Canada
Royal Alexandra Hospital, Edmonton, Alberta, T5H 3V9, Canada

¹ To whom correspondence should be addressed. e-mail: raustin{at}thrombosis.hhscr.org

Recent studies have shown a link between obesity and endoplasmic reticulum (ER) stress. Perturbations in ER homeostasis cause ER stress and activation of the unfolded protein response (UPR). Adipocyte differentiation contributes to weight gain, and we have shown that markers of ER stress/UPR activation, including GRP78, phospho-eIF2, and spliced XBP1, are upregulated during adipogenesis. Given these findings, the objective of this study was to determine whether attenuation of UPR activation by the chemical chaperone 4-phenylbutyrate (4-PBA) inhibits adipogenesis. Exposure of 3T3-L1 preadipocytes to 4-PBA in the presence of differentiation media decreased expression of ER stress markers. Concomitant with the suppression of UPR activation, 4-PBA resulted in attenuation of adipogenesis as measured by lipid accumulation and adiponectin secretion. Consistent with these in vitro findings, female C57BL/6 mice fed a high-fat diet supplemented with 4-PBA showed a significant reduction in weight gain and had reduced fat pad mass, as compared with the high-fat diet alone group. Furthermore, 4-PBA supplementation decreased GRP78 expression in the adipose tissue and lowered plasma triglyceride, glucose, leptin, and adiponectin levels without altering food intake. Taken together, these results suggest that UPR activation contributes to adipogenesis and that blocking its activation with 4-PBA prevents adipocyte differentiation and weight gain in mice.

Supplementary key words ER stress • obesity • adipocyte differentiation • 3T3-L1

Abbreviations: CHOP, C/EBP homologous protein; eIF2, -subunit of eukaryotic translational initiating factor 2; ER, endoplasmic reticulum; GRP78, glucose-regulated protein of 78-kDa; HDAC, histone deacetylase; IRE1, inositol requiring enzyme 1; MDI, isobutyl-methylxanthine dexamethasone and insulin; MEF, mouse embryonic fibroblast; 4-PBA, 4-phenylbutyric acid; PERK, PKR-like endoplasmic reticulum kinase; SREBP, sterol-regulatory element binding protein; UPR, unfolded protein response; XBP1, X-box binding protein 1

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