Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes

Interferon-gamma (IFN-gamma) is known primarily for its roles in immunologi cal responses but also has been shown to affect fat metabolism and adipocyt e gene expression. To further investigate the effects of IFN-gamma on fat c ells, we examined the effects of this cytokine on the expression of adipocy te transcription factors in 3T3-L1 adipocytes, Although IFN-gamma regulated the expression of several adipocyte transcription factors, IFN-gamma treat ment resulted in a rapid reduction of both peroxisome proliferator-activate d receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-gamma also resul ted in a decrease of both CCAAT/enhancer-binding alpha and sterol regulator y element binding protein (SREBP-1) expression. The short half-life of both the PPAR gamma mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPAR gamma in the presence of IFN-gamma. Our st udies clearly demonstrated that the IFN-gamma -induced loss of PPAR gamma p rotein is partially inhibited in the presence of two distinct proteasome in hibitors. Moreover, IFN-gamma also inhibited the transcription of PPAR gamm a, which was accompanied by a decrease in PPAR gamma mRNA accumulation. In addition, exposure to IFN-gamma resulted in a substantial increase in STAT I expression and a small increase in STAT 3 expression. IFN-gamma treatment of 3T3-L1 adipocytes (48-96 h) resulted in a substantial inhibition of ins ulin-sensitive glucose uptake. These data clearly demonstrate that IFN-gamm a treatment results in the development of insulin resistance, which is acco mpanied by the regulation of various adipocyte transcription factors, in pa rticular the synthesis and degradation of PPAR gamma.