Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance.
OBJECTIVE
We investigated subcutaneous adipose tissue expression of FOXC2 and selected genes involved in brown adipogenesis in adult human subjects in whom we have previously identified a reduced potential of precursor cell commitment to adipose-lineage differentiation in relation to insulin resistance.


METHODS
Gene expression was studied using quantitative real time polymerase chain reaction. The relation between the expression of brown adipogenic genes and the genes involved in progenitor cell commitment, adipose cell size, and insulin sensitivity in vivo was analyzed.


RESULTS
The expression of FOXC2, MASK, MAP3K5, retinoblastoma protein (pRb), peroxisome proliferator-activated protein gamma (PPARgamma), and retinoid X receptor gamma (RXRgamma) was decreased in the insulin-resistant compared with insulin-sensitive subjects, whereas PPARgamma-2 and CCAAT/enhancer binding protein alpha (C/EBPalpha) showed no differential expression. The FOXC2 expression correlated with that of Notch and Wnt signaling genes, as well as of the genes studied participating in brown adipogenesis, including MASK, MAP3K5, PPARgamma, pRb, RXRgamma, and PGC-1. A second-level correlation between PPARgamma and UCP-1 was also significant. In addition, the expression of MASK, MAP3K5, pRb, RXRgamma, and PGC-1 inversely correlated with adipose cell mass and also correlated with the glucose disposal rate in vivo.


CONCLUSIONS
Our results suggest that a reduced brown adipose phenotype is associated with insulin resistance and that a basal brown adipose phenotype may be important for maintaining normal insulin sensitivity.
Yang
Xiaolin
X
The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
Enerbäck
Sven
S
Smith
Ulf
U
D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000502:physiology*; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D051858:Forkhead Transcription Factors; D051157:Frizzled Receptors; D005786:Gene Expression Regulation / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007473:Ion Channels; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D051153:Wnt Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; C489740:FZD1 protein, human; D051858:Forkhead Transcription Factors; D051157:Frizzled Receptors; D007473:Ion Channels; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D017981:Receptors, Neurotransmitter; D015534:Trans-Activators; D014157:Transcription Factors; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D051153:Wnt Proteins; D051176:beta Catenin; C082078:mesenchyme fork head 1 protein; D012313:RNA; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3