Advanced

LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues.

Gormand, Amelie LU ; Berggreen, Christine LU ; Amar, Lahouari LU ; Henricksson, Emma; Lund, Ingrid LU ; Albinsson, Sebastian LU and Göransson, Olga LU (2014) In Journal of Molecular Endocrinology 53(1). p.117-130
Abstract
cAMP-response element-binding protein (CREB) is required for the induction of adipogenic transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs). Interestingly, it is known from other tissues that LKB1 and its substrates AMP-activated protein kinase (AMPK) and salt-inducible kinases (SIKs), negatively regulate gene expression by phosphorylating the CREB co-activator CRTC2 and class IIa histone deacetylases (HDACs), which results in their exclusion from the nucleus where they co-activate or inhibit their targets. In this study, we show that AMPK/SIK signalling is acutely attenuated during adipogenic differentiation of 3T3-L1 preadipocytes, which coincides with dephosphorylation and nuclear translocation of CRTC2 and HDAC4.... (More)
cAMP-response element-binding protein (CREB) is required for the induction of adipogenic transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs). Interestingly, it is known from other tissues that LKB1 and its substrates AMP-activated protein kinase (AMPK) and salt-inducible kinases (SIKs), negatively regulate gene expression by phosphorylating the CREB co-activator CRTC2 and class IIa histone deacetylases (HDACs), which results in their exclusion from the nucleus where they co-activate or inhibit their targets. In this study, we show that AMPK/SIK signalling is acutely attenuated during adipogenic differentiation of 3T3-L1 preadipocytes, which coincides with dephosphorylation and nuclear translocation of CRTC2 and HDAC4. When subjected to differentiation, 3T3-L1 preadipocytes in which LKB1 expression was stably reduced using shRNA (LKB1-shRNA), as well as LKB1 knockout mouse embryonic fibroblasts (LKB1-/- MEFs), differentiated more readily into adipocyte-like cells and accumulated more triglycerides compared to scrambled-shRNA 3T3-L1 cells or Wt MEFs. In addition, the phosphorylation of CRTC2 and HDAC4 was reduced, and the mRNA expression of adipogenic transcription factors C/EBPα, peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte-specific proteins such as hormone sensitive lipase (HSL), fatty acid synthase (FAS), aP2, Glut4 and adiponectin was increased in the absence of LKB1. The mRNA and protein expression of CHOP-10, a dominant negative member of the C/EBP family, was reduced in LKB1 shRNA expressing cells, providing a potential mechanism for the up-regulation of Pparg and Cebpa. These results support the hypothesis that LKB1 signalling keeps preadipocytes in their non-differentiated form. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Molecular Endocrinology
volume
53
issue
1
pages
117 - 130
publisher
Society for Endocrinology
external identifiers
  • pmid:24859970
  • wos:000345617800018
  • scopus:84904017128
ISSN
1479-6813
DOI
10.1530/JME-13-0296
language
English
LU publication?
yes
id
d32f2e8e-a6a2-4bb9-b17c-346f4ef811e9 (old id 4452580)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24859970?dopt=Abstract
date added to LUP
2014-06-06 20:42:16
date last changed
2017-07-09 03:08:25
@article{d32f2e8e-a6a2-4bb9-b17c-346f4ef811e9,
  abstract     = {cAMP-response element-binding protein (CREB) is required for the induction of adipogenic transcription factors such as CCAAT/enhancer-binding proteins (C/EBPs). Interestingly, it is known from other tissues that LKB1 and its substrates AMP-activated protein kinase (AMPK) and salt-inducible kinases (SIKs), negatively regulate gene expression by phosphorylating the CREB co-activator CRTC2 and class IIa histone deacetylases (HDACs), which results in their exclusion from the nucleus where they co-activate or inhibit their targets. In this study, we show that AMPK/SIK signalling is acutely attenuated during adipogenic differentiation of 3T3-L1 preadipocytes, which coincides with dephosphorylation and nuclear translocation of CRTC2 and HDAC4. When subjected to differentiation, 3T3-L1 preadipocytes in which LKB1 expression was stably reduced using shRNA (LKB1-shRNA), as well as LKB1 knockout mouse embryonic fibroblasts (LKB1-/- MEFs), differentiated more readily into adipocyte-like cells and accumulated more triglycerides compared to scrambled-shRNA 3T3-L1 cells or Wt MEFs. In addition, the phosphorylation of CRTC2 and HDAC4 was reduced, and the mRNA expression of adipogenic transcription factors C/EBPα, peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte-specific proteins such as hormone sensitive lipase (HSL), fatty acid synthase (FAS), aP2, Glut4 and adiponectin was increased in the absence of LKB1. The mRNA and protein expression of CHOP-10, a dominant negative member of the C/EBP family, was reduced in LKB1 shRNA expressing cells, providing a potential mechanism for the up-regulation of Pparg and Cebpa. These results support the hypothesis that LKB1 signalling keeps preadipocytes in their non-differentiated form.},
  author       = {Gormand, Amelie and Berggreen, Christine and Amar, Lahouari and Henricksson, Emma and Lund, Ingrid and Albinsson, Sebastian and Göransson, Olga},
  issn         = {1479-6813},
  language     = {eng},
  number       = {1},
  pages        = {117--130},
  publisher    = {Society for Endocrinology},
  series       = {Journal of Molecular Endocrinology},
  title        = {LKB1 signalling attenuates early events of adipogenesis and responds to adipogenic cues.},
  url          = {http://dx.doi.org/10.1530/JME-13-0296},
  volume       = {53},
  year         = {2014},
}