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

In English

Författare

Summary, in English

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.

Publiceringsår

2014

Språk

Engelska

Sidor

117-130

Publikation/Tidskrift/Serie

Journal of Molecular Endocrinology

Volym

53

Issue

1

Dokumenttyp

Artikel i tidskrift

Förlag

Society for Endocrinology

Ämne

  • Endocrinology and Diabetes

Status

Published

Forskningsgrupp

  • Protein Phosphorylation
  • Molecular Endocrinology

ISBN/ISSN/Övrigt

  • ISSN: 1479-6813