Insulin regulates the unfolded protein response in human adipose tissue

Guenther Boden, Peter Cheung, Sajad Salehi, Carol Homko, Catherine Loveland-Jones, Senthil Jayarajan, T. Peter Stein, Kevin Jon Williams, Ming Lin Liu, Carlos A. Barrero, Salim Merali

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)912-922
Number of pages11
JournalDiabetes
Volume63
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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