Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss

  1. Margaret F. Gregor1,
  2. Ling Yang1,
  3. Elisa Fabbrini2,
  4. B. Selma Mohammed2,
  5. J. Christopher Eagon2,
  6. Gökhan S. Hotamisligil1 and
  7. Samuel Klein2
  1. 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
  2. 2Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri
  1. Corresponding author: Samuel Klein, sklein{at}wustl.edu, or Gökhan S. Hotamisligil, ghotamis{at}hsph.harvard.edu

Abstract

OBJECTIVE—Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss.

RESEARCH DESIGN AND METHODS—Eleven obese men and women (BMI 51.3 ± 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers.

RESULTS—Subjects lost 39 ± 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2α (eIF2α) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2α before surgery, which was reduced in post-GBP sections.

CONCLUSIONS—This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 9 December 2008.

    M.F.G. and L.Y. contributed equally to this work.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    See accompanying commentary, p. 518.

    • Accepted November 24, 2008.
    • Received September 3, 2008.
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  1. Diabetes vol. 58 no. 3 693-700
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