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 to ad libitum fed old mice (AL-O). Our results support the notion that diminished autophagy activity with aging contributes to increased adipose tissue ER stress and inflammation.
Highlights
Chronic low-grade inflammation is a hallmark of aging that plays a crucial role in many age associated diseases [1, 2]
To investigate the role of autophagy in adipose tissue inflammation, we focused on the adipose tissue-derived stromal vascular fraction (SVF), as this is the predominant source of proinflammatory cytokines [4, 11] in fat
We analyzed mRNA expression of key autophagy-associated genes Beclin1, Atg3, Atg5, Atg7, Lc3a and Lc3b in SVFs derived from epididymal fat pads of young (4-6 months) and old (20 months) mice by real-time quantitative PCR (RT-qPCR) analysis
Summary
Chronic low-grade inflammation is a hallmark of aging that plays a crucial role in many age associated diseases [1, 2]. White adipose tissue (WAT) is recognized as a major source of chronic pro-inflammatory cytokines in aging [3, 4]. These cytokines promote insulin resistance and contribute to the development of type-2 diabetes (T2D) and other age-related diseases [5, 6]. A higher number of inflammatory M1 macrophages has been correlated with aging adipose tissue inflammation [3, 4, 8], characterization of adipose tissue cellular fractions [9, 10] has shown that preadipocytes of SVFs and are a predominant source of adipose tissue pro-inflammatory cytokines. Preadipocytes are one of the largest progenitor pools (≈15-50% in fat depots) in the body and harbor following characteristics [9]. a) Preadipocytes replicate in response to mitogens, including IGF1; b) Metabolic and secretory profiles of preadipocytes are distinct from differentiated fat cells, and vary among fat depot; c) Preadipocytes express Toll-like receptors (TLRs) and have full innate immune response capabilities; d) The gene expression profile of prewww.aging‐us.com adipocytes is closer to macrophages than fat cells; e) Activated preadipocytes can acquire macrophagelike morphology phenotypes
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