Identification of Hipk2 as an essential regulator of white fat development.
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.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Jonas
J
Sjölund
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Facundo G
FG
Pelorosso
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
David A
DA
Quigley
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Reyno
R
DelRosario
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158 abalmain@cc.ucsf.edu.
Allan
A
Balmain
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000166:cytology; D052436:Adipose Tissue, White / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D053938:DNA Fragmentation; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C112510:Cidea protein, mouse; D007328:Insulin; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C492003:Hipk2 protein, mouse; D017346:Protein Serine-Threonine Kinases