Adjuvant-induced arthritis is a chronic inflammatory illness that induces muscle wasting and decreases circulating IGF1. Eicosapentaenoic acid (EPA) and fenofibrate, a peroxisome proliferator-activated receptors α agonist, have anti-inflammatory actions and ameliorate muscle wasting in arthritic rats. The aim of this work was to elucidate whether EPA and fenofibrate administration are able to prevent the effect of arthritis on the IGF1–IGFBP system. On day 4 after adjuvant injection control, arthritic rats were gavaged with EPA (1 g/kg) or fenofibrate (300 mg/kg) until day 15 when all rats were killed. Arthritis decreased body weight gain, serum IGF1, and liver Igf1 mRNA, whereas it increased gastrocnemius Igfbp3 mRNA. EPA, but not fenofibrate, administration prevented arthritis-induced decrease in serum IGF1 and liver Igf1 mRNA. In the rats treated with EPA arthritis increased Igfbp5 mRNA in the gastrocnemius. Fenofibrate treatment decreased IGF1 and Igf1 mRNA in the liver and gastrocnemius. In arthritic rats, fenofibrate increased body weight gain and decreased gastrocnemius Igfbp3 and Igfbp5 mRNA. These data suggest that the mechanisms through which EPA and fenofibrate act on the IGF1 system and ameliorate muscle wasting in arthritic rats are different. EPA administration increased circulating levels of IGF1, whereas fenofibrate decreased the Igfbp3 and Igfbp5 in the gastrocnemius muscle.

We tested whether endotoxin (lipopolysaccharide, LPS) inhibits IGF-I gene expression in hepatocytes and the possible role of Kupffer cells and nitric oxide (NO) in this effect. LPS decreased IGF-I mRNA in hepatocyte cultures and increased the nitrite + nitrate levels in the culture medium. Furthermore, there was a negative correlation between the IGF-I mRNA and the nitrite+nitrate levels. When hepatocytes were cocultured with Kupffer cells, the inhibitory effect of LPS on IGF-I mRNA was higher than in hepatocyte cultures, but the stimulatory effect on nitrite+nitrate was similar in both conditions. The exogenous NO donated by S-nitroso-n-acetyl-d,l-penicillamide also decreased the IGF-I gene expression in hepatocyte cultures. In addition, two specific inducible NO synthase (iNOS) inhibitors, l-N6-(1-iminoethyl)lysine (l-NIL) and aminoguanidine, prevented the effect of LPS on nitrite+nitrate levels and on IGF-I gene expression in hepatocyte cultures. These data indicate that iNOS-derived NO may cause downregulation of IGF-I gene expression in hepatocytes. However, in cocultures, the iNOS inhibitor l-NIL prevented the effect of LPS on nitrite+nitrate levels, but only attenuated the LPS-induced decrease in IGF-I gene expression. We conclude that in hepatocytes, LPS-induced decrease in IGF-I is mainly due to induction of iNOS, whereas in the presence of Kupffer cells LPS inhibits IGF-I through NO release and through other inhibitory pathways.

The aim of this study was to investigate whether glucocorticoid administration had a beneficial effect on serum concentrations of insulin-like growth factor I (IGF-I) and on IGF-binding protein 3 (IGFBP-3) in rats injected with lipopolysaccharide (LPS). Adult male rats were injected with LPS or saline and pretreated with dexamethasone or saline. Dexamethasone administration decreased growth hormone (GH) receptor and IGF-I mRNA levels in the liver of control rats. LPS decreased GH receptor and IGF-I gene expression in the liver of saline-treated rats but not in the liver of dexamethasone-pretreated rats. In the kidney, GH receptor mRNA levels were not modified by dexamethasone or LPS treatment. However, LPS decreased renal IGF-I gene expression and dexamethasone pretreatment prevented this decrease. Serum concentrations of IGF-I were decreased by LPS, and dexamethasone pretreatment attenuated this effect. The gene expression of IGFBP-3 in the liver and kidney and its circulating levels were decreased by LPS. In control rats dexamethasone increased circulating IGFBP-3 and its gene expression in the liver, and decreased the proteolysis of this protein. Dexamethasone pretreatment attenuated the LPS-induced decrease in IGFBP-3 gene expression in the liver and prevented the LPS-induced decrease in IGFBP-3 gene expression in the kidney. Moreover, dexamethasone pretreatment attenuated the LPS-induced decrease in serum concentrations of IGFBP-3 and decreased the LPS-induced IGFBP-3 proteolysis in serum. In conclusion, dexamethasone pretreatment partially attenuates the inhibitory effect of LPS on serum IGF-I by blocking the decrease of its gene expression in the kidney as well as by attenuating the decrease in serum concentrations of IGFBP-3.