Role of leptin and melanocortin signaling in uremia-associated cachexia

Wai Cheung, Pin X. Yu, Brian M. Little, Roger D. Cone, Daniel Marks, Robert H. Mak

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Original languageEnglish (US)
Pages (from-to)1659-1665
Number of pages7
JournalJournal of Clinical Investigation
Volume115
Issue number6
DOIs
StatePublished - Jun 2005

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Melanocortins
Cachexia
Uremia
Leptin
Body Composition
Knockout Mice
Weight Gain
Ubiquitin C
Receptor, Melanocortin, Type 4
Leptin Receptors
Appetite
Proteasome Endopeptidase Complex
Nephrectomy
Eating
Cytokines
Diet
Gene Expression
Peptides
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Role of leptin and melanocortin signaling in uremia-associated cachexia. / Cheung, Wai; Yu, Pin X.; Little, Brian M.; Cone, Roger D.; Marks, Daniel; Mak, Robert H.

In: Journal of Clinical Investigation, Vol. 115, No. 6, 06.2005, p. 1659-1665.

Research output: Contribution to journalArticle

Cheung, Wai ; Yu, Pin X. ; Little, Brian M. ; Cone, Roger D. ; Marks, Daniel ; Mak, Robert H. / Role of leptin and melanocortin signaling in uremia-associated cachexia. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 6. pp. 1659-1665.
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