Insulin Regulates the Unfolded Protein Response in Human Adipose Tissue
- Guenther Boden1,2⇑,
- Peter Cheung1,2,
- Sajad Salehi1,2,
- Carol Homko1,2,
- Catherine Loveland-Jones3,
- Senthil Jayarajan3,
- T. Peter Stein4,
- Kevin Jon Williams1,
- Ming-Lin Liu1,
- Carlos A. Barrero5 and
- Salim Merali5
- 1Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, PA
- 2Clinical Research Center, Temple University School of Medicine, Philadelphia, PA
- 3Department of Surgery, Temple University School of Medicine, Philadelphia, PA
- 4Department of Surgery, University of Medicine and Dentistry New Jersey, Stratford, NJ
- 5Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA
- Corresponding author: Guenther Boden, .
Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼35 to ∼1,450 pmol/L). The insulin-induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple posttranslational protein modifications (acetylations, methylations, nitrosylations, succinylation, and ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutic implications, e.g., in diabetic patients treated with high doses of insulin.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0906/-/DC1.
See accompanying article, p. 841.
- Received June 11, 2013.
- Accepted October 7, 2013.
- © 2014 by the American Diabetes Association.
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