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 non-diabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼ 35 to ∼ 1450 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 post-translational protein modifications (acetylations, methylations, nitrosylations, succinylation, 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 therapeutical implications, for instance in diabetic patients treated with high doses of insulin.
- Received June 11, 2013.
- Accepted October 7, 2013.
- © 2013 by the American Diabetes Association.
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