Noradrenaline represses PPAR (peroxisome-proliferator-activated receptor) γ 2 gene expression in brown adipocytes: intracellular signalling and effects on PPARγ 2 and PPARγ 1 protein levels

PPAR (peroxisome-proliferator-activated receptor) γ is expressed in brown and white adipose tissues and is involved in the control of differentiation and proliferation. Noradrenaline stimulates brown pre-adipocyte proliferation and brown adipocyte differentiation. The aim of the present study was thus to investigate the influence of noradrenaline on PPARγ gene expression in brown adipocytes. In primary cultures of brown adipocytes, PPARγ 2 mRNA levels were 20-fold higher than PPARγ 1 mRNA levels. PPARγ expression occurred during both the proliferation and the differentiation phases, with the highest mRNA levels being found at the time of transition between the phases. PPARγ 2 mRNA levels were downregulated by noradrenaline treatment (EC50, 0.1 μM) in both proliferative and differentiating cells, with a lagtime of 1 h and lasting up to 4 h, after which expression gradually recovered. The down-regulation was β-adrenoceptor-induced and intracellularly mediated via cAMP and protein kinase A; the signalling pathway did not involve phosphoinositide 3-kinase, Src, p38 mitogenactivated protein kinase or extracellular-signal-regulated kinases 1 and 2. Treatment of the cells with the protein synthesis inhibitor cycloheximide not only abolished the noradrenaline-induced down-regulation of PPARγ 2 mRNA, but also in itself induced PPARγ 2 hyperexpression. The down-regulation was probably the result of suppression of transcription. The down-regulation of PPARγ 2 mRNA resulted in similar down-regulation of PPARγ 2 and phosphoPPARγ 2 protein levels. Remarkably, the level of PPARγ 1 protein was similar to that of PPARγ 2 (despite almost no PPARγ 1 mRNA), and the down-regulation by noradrenaline demonstrated similar kinetics to that of PPARγ 2; thus PPARγ 1 was apparently translated from the PPARγ 2 template. It is suggested that β-adrenergic stimulation via cAMP and protein kinase A represses PPARγ gene expression, leading to reduction of PPARγ 2 mRNA levels, which is then reflected in down-regulated levels of PPARγ 2, phosphoPPARγ 2 and PPARγ 1.