Modulation of adipocyte G-protein expression in cancer cachexia by a lipid-mobilizing factor (LMF).
Adipocytes isolated from cachectic mice bearing the MAC 16 tumour showed over a 3-fold increase in lipolytic response to both low concentrations of isoprenaline and a tumour-derived lipid mobilizing factor (LMF). This was reflected by an enhanced stimulation of adenylate cyclase in plasma membrane fractions of adipocytes in the presence of both factors. There was no up-regulation of adenylate cyclase in response to forskolin, suggesting that the effect arose from a change in receptor number or G-protein expression. Immunoblotting of adipocyte membranes from mice bearing the MAC16 tumour showed an increased expression of Galphas up to 10% weight loss and a reciprocal decrease in Galpha. There was also an increased expression of Galphas and a decrease in Galpha in adipose tissue from a patient with cancer-associated weight loss compared with a non-cachectic cancer patient. The changes in G-protein expression were also seen in adipose tissue of normal mice administered pure LMF as well as in 3T3L1 adipocytes in vitro. The changes in G-protein expression induced by LMF were attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). This suggests that this tumour-derived lipolytic factor acts to sensitize adipose tissue to lipolytic stimuli, and that this effect is attenuated by EPA, which is known to preserve adipose tissue in cancer cachexia.
Islam-Ali
B
B
Pharmaceutical Sciences Research Institute, Aston University, Birmingham, B4 7ET, UK.
Khan
S
S
Price
S A
SA
Tisdale
M J
MJ
D000262:Adenylyl Cyclases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D015431:Weight Loss
D001067:Appetite Depressants; D009363:Neoplasm Proteins; D010455:Peptides; C008287:lipid mobilizing substance; D005576:Colforsin; D015118:Eicosapentaenoic Acid; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol