Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPβ

C/EBP beta (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/EBP beta in brown fat, we studied the C/EBP beta-null mice. When placed in the cold, C/EBP beta(-/-) mice did not maintain body temperature. This cold-sensitive phenotype occurred, although UCP1 and PGC-1 alpha (peroxisome-proliferator-activated receptor gamma co-activator-1 alpha) gene expression was unaltered in brown fat of C/EBP beta(-/-) mice. The UCP1 gene promoter was repressed by the truncated inhibitory C/EBP beta isoform LIP (liver-enriched transcriptional inhibitory protein, the truncated inhibitory C/EBP beta isoform). Since C/EBP beta-null mice lack both C/EBP beta isoforms, active LAP (liver-enriched transcriptional activatory protein, the active C/EBP beta 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/EBP beta(-/-) 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/EBP beta(-/-) mice. LPL (lipoprotein lipase) activity was also impaired in brown fat, but not in other tissues of C/EBP beta(-/-) mice. LPL protein levels were also diminished, but this effect was independent of changes in LPL mRNA, suggesting that C/EBP beta is involved in the post-transcriptional regulation of LPL gene expression in brown fat. In summary, defective thermoregulation owing to the lack of C/EBP beta is associated with the reduced capacity to supply fatty acids as fuels to sustain brown fat thermogenesis.