Identification of Hipk2 as an essential regulator of white fat development

Proc Natl Acad Sci U S A. 2014 May 20;111(20):7373-8. doi: 10.1073/pnas.1322275111. Epub 2014 Apr 30.

Abstract

Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function. Here we have applied this network strategy to uncover a role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots, which express markers of brown and beige fat such as uncoupling protein 1 and transmembrane protein 26. These changes are accompanied by increased insulin sensitivity in Hipk2 knockout mice and reduced high-fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modeling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis.

Publication types

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

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipogenesis*
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, White / physiology*
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Differentiation
  • DNA Fragmentation
  • Diet, High-Fat
  • Female
  • Gene Expression Regulation*
  • Insulin / metabolism
  • Male
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Knockout
  • Obesity / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Transcription Factors / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Cidea protein, mouse
  • Insulin
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • Hipk2 protein, mouse
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE12248
  • GEO/GSE46077