Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes

Mol Endocrinol. 2005 Feb;19(2):399-408. doi: 10.1210/me.2004-0324. Epub 2004 Nov 4.

Abstract

Insulin-induced gene-1 (Insig-1) and its homolog Insig-2 encode closely related proteins of the endoplasmic reticulum that block proteolytic activation of sterol regulatory element binding proteins, membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes. Herein, we identified a novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] response element in the promoter region of Insig-2 gene, which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. Interestingly, 1,25-(OH)2D3 is known to directly suppress the expression of peroxisome proliferator-activated receptor gamma2 protein and inhibits adipocyte differentiation of 3T3-L1 preadipocytes and murine bone marrow stromal cells. Consistent with an idea that the antiadipogenic action of 1,25-(OH)2D3 may also involve up-regulation of Insig-2, we found that 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR, and collectively our results suggest an intriguing, new linkage between 1,25-(OH)2D3 and lipogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Animals
  • Base Sequence
  • Bone Marrow Cells / cytology
  • Calcitriol / metabolism
  • Cell Differentiation
  • DNA Primers / chemistry
  • Dimerization
  • Dose-Response Relationship, Drug
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Ligands
  • Membrane Proteins / genetics*
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • PPAR gamma / metabolism
  • Plasmids / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding
  • Receptors, Calcitriol / metabolism
  • Response Elements*
  • Retinoid X Receptors / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcriptional Activation
  • Transfection
  • Vitamin D / metabolism*

Substances

  • DNA Primers
  • INSIG2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • PPAR gamma
  • Receptors, Calcitriol
  • Retinoid X Receptors
  • Vitamin D
  • Calcitriol