title: Insulin regulates the unfolded protein response in human adipose tissue.
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.
authors.affiliation: Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.forename: Peter
authors.initials: P
authors.lastname: Cheung
authors.forename: Sajad
authors.initials: S
authors.lastname: Salehi
authors.forename: Carol
authors.initials: C
authors.lastname: Homko
authors.forename: Catherine
authors.initials: C
authors.lastname: Loveland-Jones
authors.forename: Senthil
authors.initials: S
authors.lastname: Jayarajan
authors.forename: T Peter
authors.initials: TP
authors.lastname: Stein
authors.forename: Kevin Jon
authors.initials: KJ
authors.lastname: Williams
authors.forename: Ming-Lin
authors.initials: ML
authors.lastname: Liu
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Barrero
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D054875:Ubiquitination; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics
chemical_list: D007328:Insulin; D005947:Glucose