Open AccessPropensity to endoplasmic reticulum stress in deer mouse fibroblasts predicts skin inflammation and body weight gain
Author(s) -
Youwen Zhang,
Chang-Uk Lim,
Vitali Sikirzhytski,
Asieh Naderi,
Ioulia Chatzistamou,
Hippokratis Kiaris
Publication year - 2021
Publication title -
disease models and mechanisms
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.327
H-Index - 83
eISSN - 1754-8411
pISSN - 1754-8403
DOI - 10.1242/dmm.049113
Subject(s) - endoplasmic reticulum , unfolded protein response , inflammation , weight gain , proinflammatory cytokine , pathogenesis , body weight , biology , transcriptome , endocrinology , secretion , obesity , medicine , microbiology and biotechnology , immunology , genetics , gene , gene expression
The unfolded protein response (UPR) is involved in the pathogenesis of metabolic disorders, yet whether variations in the UPR among individuals influence the propensity for metabolic disease remains unexplored. Using outbred deer mice as a model, we show that the intensity of UPR in fibroblasts isolated early in life predicts the extent of body weight gain after high-fat diet (HFD) administration. Contrary to those with intense UPR, animals with moderate UPR in fibroblasts and therefore displaying compromised stress resolution did not gain body weight but developed inflammation, especially in the skin, after HFD administration. Fibroblasts emerged as potent modifiers of this differential responsiveness to HFD, as indicated by the comparison of the UPR profiles of fibroblasts responding to fatty acids in vitro, by correlation analyses between UPR and proinflammatory cytokine-associated transcriptomes, and by BiP (also known as HSPA5) immunolocalization in skin lesions from animals receiving HFD. These results suggest that the UPR operates as a modifier of an individual's propensity for body weight gain in a manner that, at least in part, involves the regulation of an inflammatory response by skin fibroblasts. This article has an associated First Person interview with the first author of the paper.