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Journal of Lipid Research, Vol. 48, 1905-1914, September 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease

Margaret F. Gregor and Gökhan S. Hotamisligil¹

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115

Published, JLR Papers in Press, May 9, 2007.

¹ To whom correspondence should be addressed. e-mail: ghotamis{at}hsph.harvard.edu

In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis.

Supplementary key words obesity • type 2 diabetes • unfolded protein response • chaperones • inflammation • lipid • fat cells

Abbreviations: ASK1, apoptosis signal-regulating kinase 1; ATF-6, activating transcription factor-6; CHOP, C/EBP homologous protein; EDEM, ER degradation-enhancing -mannosidase-like protein; eIF2, eukaryotic translational initiation factor 2; ER, endoplasmic reticulum; ERdj4, endoplasmic reticulum-resident DNAj homolog 4; ERO1, ER redox control for endoplasmic reticulum oxidoreductin; GADD34, growth arrest and DNA damage-inducible protein; IKB, inhibitor of NKB; IKK-NFB, IKB kinase nuclear factor B; IL-6, interleukin-6; IRE-1, inositol-requiring enzyme-1; IRS-1, insulin receptor substrate 1; JNK, c-jun N-terminal kinase; mTOR, mammalian target of rapamycin; NFB, nuclear factor B; ORP150, oxygen-regulated protein; PBA, phenyl butyric acid; PDI, protein disulfide isomerase; PERK, PKR-like eukaryotic initiation factor 2 kinase; PPAR, peroxisome proliferator-activated receptor ; ROS, reactive oxygen species; SREBP, sterol-regulatory element binding protein; TNF-, tumor necrosis factor-; TG, triglyceride; TRAF2, tumor necrosis factor receptor-associated factor 2; Trb3, Tribbles 3/SKIP 3; TUDCA, taurine-conjugated ursodeoxycholic acid; UPR, unfolded protein response; XBP-1, X-box protein 1

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