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 during fat catabolism in cancer cachexia.
Bing
C
C
Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool L69 3G, UK. bing@iv.ac.uk
Russell
S T
ST
Beckett
E E
EE
Collins
P
P
Taylor
S
S
Barraclough
R
R
Tisdale
M J
MJ
Williams
G
G
D000230:Adenocarcinoma / Q000652:urine*; D002001:Adipose Tissue, Brown / Q000187:drug effects; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D007473:Ion Channels; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D015854:Up-Regulation
D002352:Carrier Proteins; D017931:DNA Primers; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; C000604371:UCP1 protein, human; C000604389:UCP2 protein, human; C000604372:Ucp1 protein, mouse; C000604390:Ucp2 protein, mouse; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; C008287:lipid mobilizing substance