Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging

J Gerontol A Biol Sci Med Sci. 2015 Nov;70(11):1320-9. doi: 10.1093/gerona/glu186. Epub 2014 Oct 16.

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.

Keywords: Adipose tissue; Aging; Chemical chaperones.; ER stress response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology*
  • Age Factors
  • Animals
  • Cell Culture Techniques
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress / physiology*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Enzyme Inhibitors
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Inflammation
  • Macrophages / physiology*
  • Male
  • Mice
  • Phenylbutyrates
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / metabolism
  • Regulatory Factor X Transcription Factors
  • Stromal Cells / physiology*
  • Thapsigargin
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • X-Box Binding Protein 1

Substances

  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Ddit3 protein, mouse
  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • Phenylbutyrates
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Transcription Factor CHOP
  • Thapsigargin
  • 4-phenylbutyric acid
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • molecular chaperone GRP78