title: Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging.
abstract: Adipose tissue inflammation has been linked to age-related metabolic diseases. However, the underlying mechanisms are poorly understood. Adipose tissue inflammation and insulin resistance in diet associated obesity has been correlated with aberrant endoplasmic reticulum (ER) stress. This study was undertaken to test our hypothesis that increased ER stress response contributes to age-associated adipose tissue inflammation. We found elevated ER stress response in adipose tissue of old (18-20 months) compared to young (4-6 months) mice. Elevated ER stress markers BIP (GRP78), CHOP, cleaved-ATF-6, phospho-IRE1α, and XBP-1 were observed in old compared to young adipose tissue stromal cells. Additionally, old adipose tissue stromal cells were more sensitive to an ER stress inducer, thapsigargin. Similar experiments with adipose tissue macrophages showed elevated Chop and Bip expression in old adipose tissue macrophages when induced with thapsigargin. Treatment of chemical chaperone 4-phenyle-butyric acid alleviated ER stress in adipose tissue stromal cells and adipose tissue macrophages and attenuated the production of IL-6 and MCP-1 by adipose tissue stromal cells, and TNF-α by adipose tissue macrophages from both young and old mice. Finally, old mice fed with 4-phenyle-butyric acid have reduced expression of ER stress and inflammatory cytokine genes. Our data suggests that an exaggerated ER stress response in aging adipose tissue contributes to age-associated inflammation that can be mitigated by treatment with chemical chaperones.
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Amiya Kumar
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Garg
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Theresa
authors.initials: T
authors.lastname: Mau
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Martin
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Geriatrics and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor. Geriatric Research, Education and Clinical Care Center (GRECC), VA Ann Arbor Health System, Michigan. amiyag@umich.edu.
authors.forename: Raymond
authors.initials: R
authors.lastname: Yung
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology*; D000367:Age Factors; D000818:Animals; D018929:Cell Culture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D010654:Phenylbutyrates; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D017154:Stromal Cells / Q000502:physiology*; D019284:Thapsigargin; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010654:Phenylbutyrates; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C075773:4-phenylbutyric acid; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Adipose tissue; Aging; Chemical chaperones.; ER stress response