title: Impaired autophagy activity is linked to elevated ER-stress and inflammation in aging adipose tissue.
abstract: Adipose tissue dysfunction in aging is associated with inflammation, metabolic syndrome and other diseases. We propose that impaired protein homeostasis due to compromised lysosomal degradation (micro-autophagy) might promote aberrant ER stress response and inflammation in aging adipose tissue. Using C57BL/6 mouse model, we demonstrate that adipose tissue-derived stromal vascular fraction (SVF) cells from old (18-20 months) mice have reduced expression of autophagy markers as compared to the younger (4-6 months) cohort. Elevated expressions of ER-stress marker CHOP and autophagy substrate SQSTM1/p62 are observed in old SVFs compared to young, when treated with either vehicle or with thapsigargin (Tg), an ER stress inducer. Treatment with bafilomycin A1 (Baf), a vacuolar-type H (+)-ATPase, or Tg elevated expressions of CHOP, and SQSTM1/p62 and LC-3-II, in 3T3-L1-preadipocytes. We also demonstrate impaired autophagy activity in old SVFs by analyzing increased accumulation of autophagy substrates LC3-II and p62. Compromised autophagy activity in old SVFs is correlated with enhanced release of pro-inflammatory cytokines IL-6 and MCP-1. Finally, SVFs from calorie restricted old mice (CR-O) have shown enhanced autophagy activity compared toad libitumfed old mice (AL-O). Our results support the notion that diminished autophagy activity with aging contributes to increased adipose tissue ER stress and inflammation.
authors: Division of Geriatric- and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Amiya Kumar
authors: AK
authors: Ghosh
authors: Division of Geriatric- and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Theresa
authors: T
authors: Mau
authors: Division of Geriatric- and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Martin
authors: M
authors: O'Brien
authors: Division of Geriatric- and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Sanjay
authors: S
authors: Garg
authors: Division of Geriatric- and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Geriatric Research, Education and Clinical Care Center (GRECC), VA Ann Arbor Health System, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Raymond
authors: R
authors: Yung
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D019284:Thapsigargin
keywords: ER-Stress; adipose tissue; aging; autophagy; inflammation