title: Inhibition of cisplatin-induced lipid catabolism and weight loss by ghrelin in male mice.
abstract: Cachexia, defined as an involuntary weight loss ≥ 5%, is a serious and dose-limiting side effect of chemotherapy that decreases survival in cancer patients. Alterations in lipid metabolism are thought to cause the lipodystrophy commonly associated with cachexia. Ghrelin has been proposed to ameliorate the alterations in lipid metabolism due to its orexigenic and anabolic properties. However, the mechanisms of action through which ghrelin could potentially ameliorate chemotherapy-associated cachexia have not been elucidated. The objectives of this study were to identify mechanisms by which the chemotherapeutic agent cisplatin alters lipid metabolism and to establish the role of ghrelin in reversing cachexia. Cisplatin-induced weight and fat loss were prevented by ghrelin. Cisplatin increased markers of lipolysis in white adipose tissue (WAT) and of β-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, β-oxidation, and lipogenesis in WAT and muscle. Pair-feeding experiments demonstrated that the effects of cisplatin and ghrelin on lipogenesis, but not on lipolysis and β-oxidation, were due to a reduction in food intake. Thus, ghrelin prevents cisplatin-induced weight and fat loss by restoring adipose tissue functionality. An increase in caloric intake further enhances the anabolic effects of ghrelin.
authors.affiliation: Department of Medicine and Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA. jgarcia1@bcm.edu
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.forename: Ji-an
authors.initials: JA
authors.lastname: Chen
authors.forename: Bobby
authors.initials: B
authors.lastname: Guillory
authors.forename: Anriada
authors.initials: A
authors.lastname: Nassif
authors.forename: Victor
authors.initials: V
authors.lastname: Papusha
authors.forename: Joanna
authors.initials: J
authors.lastname: Smiechowska
authors.forename: Mark
authors.initials: M
authors.lastname: Asnicar
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019167:Appetite Stimulants / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002100:Cachexia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000009:adverse effects*; D002149:Energy Intake / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054439:Ghrelin / Q000627:therapeutic use*; D050155:Lipogenesis / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011897:Random Allocation; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019167:Appetite Stimulants; D015415:Biomarkers; D054439:Ghrelin; D002945:Cisplatin