Expression of uncoupling proteins-1,-2 and-3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor

The abnormalities of lipid metabolism observed in cancer cachexia may be induced by a lipid-mobilizing factor produced by adenocarcinomas. The specific molecules and metabolic pathways that mediate the actions of lipid-mobilizing factor are not known. The mitochondrial uncoupling proteins-1, -2 and -3 are suggested to play essential roles in energy dissipation and disposal of excess lipid. Here, we studied the effects of lipid-mobilizing factor on the expression of uncoupling proteins-1, -2 and -3 in normal mice, Lipid-mobilizing factor isolated from the urine of cancer patients was injected intravenously Into mice over a 52-h period, while vehicle was similarly given to controls, Lipid-mobilizing factor, caused significant reductions in body weight (- 10%, P=0.03) and fat mass (- 20% P < 0.01) accompanied by a marked decrease in plasma leptin (- 59%, P < 0.01) and heavy lipid deposition in the liver, In brown adipose tissue, uncoupling protein-1 mRNA levels were elevated in lipid-mobilizing factor-treated mice (+96%, P < 0.01), as were uncoupling proteins-2 and -3 (+57% and +37%, both P < 0,05). Lipid-mobilizing factor increased uncoupling protein-2 mRNA in both skeletal muscle (+146%. P < 0.05) and liver (+142%, P=0.03), The protein levels of uncoupling protein-1 in brown adipose tissue and uncoupling protein-2 in liver were also increased with lipid-mobilizing factor administration (+49% and +67%, both P=0.02). Upregulation by lipid-mobilizing factor of uncoupling proteins-1, -2 and -3 in brown adipose tissue. and of uncoupling protein-2 in skeletal muscle and liver, suggests that these uncoupling proteins may serve to utilize excess lipid mobilized dunng fat catabolism in cancer cachexia.