Early induction of pyruvate dehydrogenase kinase 4 by retinoic acids in adipocytes

Mol Nutr Food Res. 2017 May;61(5). doi: 10.1002/mnfr.201600920. Epub 2017 Feb 27.


Scope: Vitamin A and its metabolites, such as retinoic acids (RA), are related to metabolic diseases, in particular insulin resistance and obesity. Here, we studied the roles of 9-cis RA and all-trans RA on the regulation of pyruvate dehydrogenase kinase 4 (PDK4), an enzyme involved in fatty acid reesterification, which is a crucial metabolic pathway in adipose tissue (AT) lipid homeostasis.

Methods and results: 9-cis RA and all-trans RA treatment of human and murine AT explants, as well as adipocytes (3T3-F442A cell line) induces PDK4 expression both at the mRNA and the protein level, via a transcriptional mechanism. Using site-directed mutagenesis and chomatin immuno-precipitation, we showed that this activation involves two new RA responsive elements in the Pdk4 promoter, RAREa (DR1: -125/-112) and RAREb (DR1: -86/-73), specific to AT. Furthermore, even though endogeneous Pdk4 gene was upregulated by RA in Fao cells, a rat hepatoma cell line, the induction did not occur through the newly found RAREs.

Conclusion: In this study, we showed that adipocyte PDK4 gene is a new target of the vitamin A derived RA and might participate to the reduced fatty acid efflux from the adipocyte, a step that plays an important role in the developement of metabolic diseases.

Keywords: Adipose tissue; Glyceroneogenesis; Pyruvate dehydrogenase kinase 4; Retinoic acids.

MeSH terms

  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Adult
  • Alitretinoin
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Mutagenesis, Site-Directed
  • NIH 3T3 Cells
  • Promoter Regions, Genetic
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Tretinoin / pharmacology*


  • Alitretinoin
  • Tretinoin
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4