title: Association between arsenic suppression of adipogenesis and induction of CHOP10 via the endoplasmic reticulum stress response.
abstract: BACKGROUND
  There is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis.
  
  
  OBJECTIVE
  We sought to determine the mechanisms of arsenic suppression of adipogenesis.
  
  
  METHODS
  The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).
  
  
  RESULTS
  Exposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ≤ 5 μM), inorganic arsenate (≤ 20 μM), trivalent monomethylated arsenic (MMA3+, ≤ 1 μM), and trivalent dimethylated arsenic (DMA3+, ≤ 2 μM) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein β (C/EBPβ), which regulates the transcription of peroxisome proliferator-activated receptor γ and C/EBPα.
  
  
  CONCLUSIONS
  Low-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBPβ transcriptional activity, thus suppressing adipogenesis. Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.
authors.affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Kathy
authors.initials: K
authors.lastname: Yarborough
authors.forename: Weidong
authors.initials: W
authors.lastname: Qu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D015153:Blotting, Western; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000096:biosynthesis*
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D001151:Arsenic