title: A pegylated leptin antagonist ameliorates CKD-associated cachexia in mice.
abstract: Elevated serum leptin levels correlate with inflammation and predict changes in lean body mass in patients with CKD, and activation of the melanocortin system by leptin signaling mediates the pathophysiology of CKD-associated cachexia. We tested whether treatment with a pegylated leptin receptor antagonist (PLA) attenuates cachexia in mice with CKD. CKD and Sham mice received vehicle or PLA (2 or 7 mg/kg per day). At these doses, PLA did not influence serum leptin levels in mice. Treatment with 7 mg/kg per day PLA stimulated appetite and weight gain, improved lean mass and muscle function, reduced energy expenditure, and normalized the levels of hepatic TNF-α and IL-6 mRNA in mice with CKD. Furthermore, treatment with 7 mg/kg per day PLA attenuated the CKD-associated increase in the transcriptional and protein abundance of uncoupling proteins that mediates thermogenesis, and it normalized the molecular signatures of processes associated with muscle wasting in CKD, including proteolysis, myogenesis and muscle regeneration, and expression of proinflammatory muscle cytokines, such as IL-1α, -1β, and -6 and TNF-α. Our results suggest that leptin antagonism may represent a viable therapeutic strategy for cachexia in CKD.
authors.affiliation: Division of Pediatric Nephrology, University of California, San Diego, La Jolla, California;
authors.forename: Wai W
authors.initials: WW
authors.lastname: Cheung
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Sujana S
authors.initials: SS
authors.lastname: Gunta
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.forename: Rinat
authors.initials: R
authors.lastname: Tabakman
authors.forename: Leah N
authors.initials: LN
authors.lastname: Klapper
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mak
mesh_terms: D000818:Animals; D000855:Anorexia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D002100:Cachexia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors*; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse