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Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects

Endocrine Section (N.K.S., S.K.D., A.K.M., O.G.H., W.S.C., P.A.K., N.R., A.Y.-B., S.C.E.), Medicine and Research Services, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72114-1706; and Division of Endocrinology and Metabolism (N.K.S., S.K.D., A.K.M., O.G.H., W.S.C., P.A.K., N.R., A.Y.-B., S.C.E.), Departments of Internal Medicine and Biostatistics (H.J.S.), College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Steven C. Elbein, M.D., Professor of Medicine, University of Arkansas for Medical Sciences, Endocrinology 111J-1/LR, John L. McClellan Memorial Veterans Hospital, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: elbeinstevenc{at}uams.edu.

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 (S_I) 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 2, 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 2 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 S_I.

Conclusions: Multiple markers of ER stress are activated in human adipose with obesity, particularly for protective chaperones downstream of activating transcription factor 6.

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