Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPbeta.
C/EBPbeta (CCAAT/enhancer-binding protein beta) is a transcriptional regulator of the UCP1 (uncoupling protein-1) gene, the specific marker gene of brown adipocytes that is responsible for their thermogenic capacity. To investigate the role of C/EBPbeta in brown fat, we studied the C/EBPbeta-null mice. When placed in the cold, C/EBPbeta(-/-) mice did not maintain body temperature. This cold-sensitive phenotype occurred, although UCP1 and PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) gene expression was unaltered in brown fat of C/EBPbeta(-/-) mice. The UCP1 gene promoter was repressed by the truncated inhibitory C/EBPbeta isoform LIP (liver-enriched transcriptional inhibitory protein, the truncated inhibitory C/EBPbeta isoform). Since C/EBPbeta-null mice lack both C/EBPbeta isoforms, active LAP (liver-enriched transcriptional activatory protein, the active C/EBPbeta isoform) and LIP, the absence of LIP may have a stronger effect than the absence of LAP upon UCP1 gene expression. Gene expression for UCP2 and UCP3 was not impaired in all tissues analysed. In primary brown adipocytes from C/EBPbeta(-/-) mice, induction of gene expression by noradrenaline was preserved. In contrast, the expression of genes related to lipid storage was impaired, as was the amount of triacylglycerol mobilized after acute cold exposure in brown fat from C/EBPbeta(-/-) mice. LPL (lipoprotein lipase) activity was also impaired in brown fat, but not in other tissues of C/EBPbeta(-/-) mice. LPL protein levels were also diminished, but this effect was independent of changes in LPL mRNA, suggesting that C/EBPbeta is involved in the post-transcriptional regulation of LPL gene expression in brown fat. In summary, defective thermoregulation owing to the lack of C/EBPbeta is associated with the reduced capacity to supply fatty acids as fuels to sustain brown fat thermogenesis.
Carmona
M Carmen
MC
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, E-08028-Barcelona, Catalunya, Spain.
Hondares
Elayne
E
Rodríguez de la Concepción
M Luisa
ML
Rodríguez-Sureda
Víctor
V
Peinado-Onsurbe
Julia
J
Poli
Valeria
V
Iglesias
Roser
R
Villarroya
Francesc
F
Giralt
Marta
M
D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D001835:Body Weight; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D003080:Cold Temperature; D003576:Electron Transport Complex IV / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D005819:Genetic Markers / Q000235:genetics; D007473:Ion Channels; D050356:Lipid Metabolism / Q000187:drug effects*; D008071:Lipoprotein Lipase / Q000032:analysis / Q000097:blood / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D024101:Mitochondrial Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1
D018663:Adrenergic Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D002352:Carrier Proteins; D005227:Fatty Acids; D005819:Genetic Markers; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D014280:Triglycerides; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D051743:CCAAT-Enhancer-Binding Protein-delta; D003576:Electron Transport Complex IV; D008071:Lipoprotein Lipase