Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects

Neeraj K. Sharma, Swapan K. Das, Ashis K. Mondal, Oksana G. Hackney, Winston S. Chu, Philip A. Kern, Neda Rasouli, Horace J. Spencer, Aiwei Yao-Borengasser, Steven C. Elbein

Research output: Contribution to journalArticlepeer-review

223 Scopus citations


Objective: Adipocyte and hepatocyte endoplasmic reticulum (ER) stress response is activated in dietary and genetic models of obesity in mice. We hypothesized that ER stress was also activated and associated with reduced insulin sensitivity (SI) in human obesity. Research Design and Methods: We recruited 78 healthy, nondiabetic individuals over a spectrum of body mass index (BMI) who underwent oral and iv glucose tolerance tests, and fasting sc adipose and muscle biopsies. We tested expression of 18 genes and levels of total and phosphorylated eukaryotic initiation factor 2α, c-jun, and c-Jun N-terminal kinase 1 in adipose tissue. We compared gene expression in stromal vascular and adipocyte fractions in paired samples from 22 individuals, and tested clustering on gene and protein markers. Results: Adipocyte expression of most markers of ER stress, including chaperones downstream of activating transcription factor 6, were significantly correlated with BMI and percent fat (r > 0.5; P < 0.00001). Phosphorylation of eukaryotic initiation factor 2α but not of c-Jun N-terminal kinase 1 or c-jun was increased with obesity. ER stress response (as elsewhere) was also increased with obesity in a second set of 86 individuals, and in the combined sample (n = 161). The increase was only partially attributable to the stromal vascular fraction and macrophage infiltration. ER stress markers were only modestly correlated with S I. Clustering algorithms supported ER stress activation with high BMI but not low SI. Conclusions: Multiple markers of ER stress are activated in human adipose with obesity, particularly for protective chaperones downstream of activating transcription factor 6α.

Original languageEnglish
Pages (from-to)4532-4541
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 2008

Bibliographical note

Funding Information:
This work was supported by the Research Service of the Department of Veterans Affairs (Merit funds to S.C.E., P.A.K., and N.R.; Resource Enhancement and Protection Program funds), and in part by the General Clinical Research Center (Grant M01RR14288 from National Center for Research Resources, National Institutes of Health to the University of Arkansas for Medical Sciences).

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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