Modulation of melanocortin signaling ameliorates uremic cachexia

Kidney Int. 2008 Jul;74(2):180-6. doi: 10.1038/ki.2008.150. Epub 2008 Apr 23.


Insulin-like growth factor (IGF)-I increases muscle mass while myostatin inhibits its development. Muscle wasting is common in patients with uremic cachexia and may be due to imbalance of this regulation. We had proposed a central mechanism involving leptin and melanocortin signaling in the pathogenesis of uremic cachexia since agouti-related peptide (AgRP), a melanocortin-4 receptor antagonist, reduced uremic cachexia. Here we found that injection of AgRP into the cerebral ventricles resulted in a gain of body mass and improved metabolic rate regulation in a mouse model of uremic cachexia. These salutary effects occurred independent of increased protein and calorie intake. Myostatin mRNA and protein concentrations were increased while those of IGF-I were decreased in the skeletal muscle of uremic mice. AgRP treatment partially corrected these uremia-induced changes. Suppressor of cytokine signaling-2 gene expression (SOCS2) was significantly increased in uremic animals and AgRP reduced this expression. We suggest that AgRP improves uremic cachexia and muscle wasting by a peripheral mechanism involving the balance between myostatin and IGF-I.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / administration & dosage
  • Animals
  • Appetite Regulation
  • Cachexia / etiology
  • Cachexia / metabolism*
  • Cachexia / prevention & control
  • Chronic Disease
  • Gene Expression / drug effects
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Leptin / metabolism
  • Male
  • Melanocortins / antagonists & inhibitors
  • Melanocortins / genetics
  • Melanocortins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Muscular Atrophy / etiology
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / prevention & control
  • Myostatin
  • Nephrectomy
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Transforming Growth Factor beta / genetics
  • Uremia / complications
  • Uremia / metabolism*


  • Agouti-Related Protein
  • Leptin
  • MSTN protein, human
  • Melanocortins
  • Mstn protein, mouse
  • Myostatin
  • RNA, Messenger
  • Socs2 protein, mouse
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transforming Growth Factor beta
  • Insulin-Like Growth Factor I