title: ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice.
abstract: OBJECTIVE
  Although obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue, it is not known how UPR signalling affects adipogenesis. To test whether signalling through protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 alpha (PERK/eIF2α) or inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) is required for adipogenesis, we studied the role of UPR signalling in adipocyte differentiation in vitro and in vivo in mice.
  
  
  METHODS
  The role of UPR signalling in adipogenesis was investigated using 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) by activation or inhibition of PERK-mediated phosphorylation of the eIF2α- and IRE1α-mediated splicing of Xbp1 mRNA. Body weight change, fat mass composition and adipocyte number and size were measured in wild-type and genetically engineered mice fed a control or high-fat diet (HFD).
  
  
  RESULTS
  ER stress repressed adipocyte differentiation in 3T3-L1 cells. Impaired eIF2α phosphorylation enhanced adipocyte differentiation in MEFs, as well as in mice. In contrast, increased eIF2α phosphorylation reduced adipocyte differentiation in 3T3-L1 cells. Forced production of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), a downstream target of eIF2α phosphorylation, inhibited adipogenesis in 3T3-L1 cells. Mice with deletion of Chop (also known as Ddit3) (Chop (-/-)) gained more fat mass than wild-type mice on HFD. In addition, Chop deletion in genetically obese Lepr (db/db) mice increased body fat mass without altering adipocyte size. In contrast to the eIF2α-CHOP pathway, activation or deletion of Ire1a (also known as Ern1) did not alter adipocyte differentiation in 3T3-L1 cells.
  
  
  CONCLUSIONS
  These results demonstrate that eIF2α-CHOP suppresses adipogenesis and limits expansion of fat mass in vivo in mice, rendering this pathway a potential therapeutic target.
authors: Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037-1062, USA.
authors: J
authors: J
authors: Han
authors: R
authors: R
authors: Murthy
authors: B
authors: B
authors: Wood
authors: B
authors: B
authors: Song
authors: S
authors: S
authors: Wang
authors: B
authors: B
authors: Sun
authors: H
authors: H
authors: Malhi
authors: R J
authors: RJ
authors: Kaufman
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D001823:Body Composition; D002454:Cell Differentiation; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D051742:Transcription Factor CHOP; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases