ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice

J. Han, R. Murthy, B. Wood, B. Song, S. Wang, B. Sun, Harmeet M Malhi, R. J. Kaufman

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Aims/hypothesis: 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/interpretation: 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.

Original languageEnglish (US)
Pages (from-to)911-924
Number of pages14
JournalDiabetologia
Volume56
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Transcription Factor CHOP
Adipogenesis
Endoplasmic Reticulum Stress
Adipocytes
3T3-L1 Cells
Unfolded Protein Response
Phosphorylation
Fats
High Fat Diet
Adipose Tissue
Fibroblasts
Eukaryotic Initiation Factor-2
CCAAT-Enhancer-Binding Proteins
Body Weight Changes
Inositol
Endoplasmic Reticulum
Protein Kinases
Phosphotransferases
Obesity
RNA

Keywords

  • Adipocyte
  • C/EBP homologous protein (CHOP)
  • eIF2α phosphorylation
  • Endoplasmic reticulum
  • Unfolded protein response (UPR)

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Han, J., Murthy, R., Wood, B., Song, B., Wang, S., Sun, B., ... Kaufman, R. J. (2013). ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice. Diabetologia, 56(4), 911-924. https://doi.org/10.1007/s00125-012-2809-5

ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice. / Han, J.; Murthy, R.; Wood, B.; Song, B.; Wang, S.; Sun, B.; Malhi, Harmeet M; Kaufman, R. J.

In: Diabetologia, Vol. 56, No. 4, 04.2013, p. 911-924.

Research output: Contribution to journalArticle

Han, J, Murthy, R, Wood, B, Song, B, Wang, S, Sun, B, Malhi, HM & Kaufman, RJ 2013, 'ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice', Diabetologia, vol. 56, no. 4, pp. 911-924. https://doi.org/10.1007/s00125-012-2809-5
Han, J. ; Murthy, R. ; Wood, B. ; Song, B. ; Wang, S. ; Sun, B. ; Malhi, Harmeet M ; Kaufman, R. J. / ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice. In: Diabetologia. 2013 ; Vol. 56, No. 4. pp. 911-924.
@article{5cdc1ee69f7d456590c9e75a10c303f4,
title = "ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice",
abstract = "Aims/hypothesis: 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/interpretation: 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.",
keywords = "Adipocyte, C/EBP homologous protein (CHOP), eIF2α phosphorylation, Endoplasmic reticulum, Unfolded protein response (UPR)",
author = "J. Han and R. Murthy and B. Wood and B. Song and S. Wang and B. Sun and Malhi, {Harmeet M} and Kaufman, {R. J.}",
year = "2013",
month = "4",
doi = "10.1007/s00125-012-2809-5",
language = "English (US)",
volume = "56",
pages = "911--924",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice

AU - Han, J.

AU - Murthy, R.

AU - Wood, B.

AU - Song, B.

AU - Wang, S.

AU - Sun, B.

AU - Malhi, Harmeet M

AU - Kaufman, R. J.

PY - 2013/4

Y1 - 2013/4

N2 - Aims/hypothesis: 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/interpretation: 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.

AB - Aims/hypothesis: 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/interpretation: 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.

KW - Adipocyte

KW - C/EBP homologous protein (CHOP)

KW - eIF2α phosphorylation

KW - Endoplasmic reticulum

KW - Unfolded protein response (UPR)

UR - http://www.scopus.com/inward/record.url?scp=84876485565&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876485565&partnerID=8YFLogxK

U2 - 10.1007/s00125-012-2809-5

DO - 10.1007/s00125-012-2809-5

M3 - Article

C2 - 23314846

AN - SCOPUS:84876485565

VL - 56

SP - 911

EP - 924

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -