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, H.
AU - Kaufman, R. J.
N1 - Funding Information:
Funding This work was supported by NIH grants DK042394, DK088227, DK093074, HL052173 and HL057346 (R. J. Kaufman). Portions of this work were supported by University of Michigan CCMB Pilot Grant (J. Han).
Funding Information:
Acknowledgements We thank A. Kyle (University of Calgary) and J. Mitchell (University of Michigan) for assistance with manuscript preparation and the members of the Kaufman laboratory for critical input. We thank H. Mori (University of Michigan) for invaluable technical assistance and J. Patterson (MannKind Corporation) for the IRE1α inhibitor. This work used the Animal Phenotyping core of the Michigan Diabetes Research and Training Center funded by DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases. We thank ARIAD Pharmaceuticals, Inc. for providing AP20187.
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 - Endoplasmic reticulum
KW - Unfolded protein response (UPR)
KW - eIF2α phosphorylation
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U2 - 10.1007/s00125-012-2809-5
DO - 10.1007/s00125-012-2809-5
M3 - Article
C2 - 23314846
AN - SCOPUS:84876485565
SN - 0012-186X
VL - 56
SP - 911
EP - 924
JO - Diabetologia
JF - Diabetologia
IS - 4
ER -