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J Mol Endocrinol. 2014 Aug;53(1):117-30. doi: 10.1530/JME-13-0296. Epub 2014 May 23.

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

Author information

1
Department of Experimental Medical ScienceLund University, BMC C11, 221 84 Lund, SwedenDepartment of BiomedicineKarolinska Institute, Stockholm, Sweden.
2
Department of Experimental Medical ScienceLund University, BMC C11, 221 84 Lund, SwedenDepartment of BiomedicineKarolinska Institute, Stockholm, Sweden Olga.Goransson@med.lu.se.

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 studies in 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 the dephosphorylation and nuclear translocation of CRTC2 and HDAC4. When subjected to differentiation, 3T3-L1 preadipocytes in which the expression of LKB1 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 with scrambled-shRNA-expressing 3T3-L1 cells or Wt MEFs. In addition, the phosphorylation of CRTC2 and HDAC4 was reduced, and the mRNA expression of adipogenic transcription factors Cebpa, peroxisome proliferator-activated receptor γ (Pparg) 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 Ddit3/CHOP10, 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 expression. These results support the hypothesis that LKB1 signalling keeps preadipocytes in their non-differentiated form.

KEYWORDS:

AMPK; CRTC2; HDACs; LKB1; SIKs; adipogenesis

PMID:
24859970
DOI:
10.1530/JME-13-0296
[Indexed for MEDLINE]

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