title: Interactions of amylinergic and melanocortinergic systems in the control of food intake and body weight in rodents.
abstract: OBJECTIVE
  Amylinergic and melanocortinergic systems have each been implicated in energy balance regulation. We examined the interactive effects of both systems using gene knockout and pharmacological approaches.
  
  
  METHODS
  Acute food consumption was measured in overnight fasted male wild-type (WT) and melanocortin-4 receptor (MC-4R) deficient rats and in male and female WT and amylin knockout mice (AmyKO). Changes in food intake, body weight and composition in male WT and MC-4R deficient rats and in male diet-induced obese (DIO) rats. Pharmacological treatments included either rat amylin, murine leptin and/or the MC-4R agonist, Ac-R[CEH-dF-RWC]-amide.
  
  
  RESULTS
  Amylin (10 µg/kg, IP) decreased food intake in WT but not in MC-4R deficient rats (30 and 60 min post-injection). Ac-R[CEH-dF-RWC]-amide (100 µg/kg, IP) suppressed food intake similarly in male WT and AmyKO, but was ineffective in female AmyKO. Amylin (50 µg/kg/day for 28 days) and leptin (125 µg/kg/day) synergistically reduced food intake and body weight in WT and MC-4R deficient rats to a similar extent. Amylin (100 µg/kg) combined with Ac-R[CEH-dF-RWC]-amide (100 µg/kg, IP) decreased acute food intake over 3 h to a greater extent than either agent alone in fasted mice. In DIO rats, additive anorexigenic, weight- and fat-lowering effects were observed over 12 days with the combination of rat amylin (50 µg/kg/day) and Ac-R[CEH-dF-RWC]-amide (2.3 mg/kg, SC injected daily).
  
  
  CONCLUSIONS
  Although amylin's acute anorexigenic effects are somewhat blunted in MC-4R deficiency and those of MC-4R agonism in amylin deficiency, these effects are surmountable with pharmacological administration lending therapeutic potential to combined amylin/melanocortin agonism for obesity.
authors.affiliation: Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, CA 92121, USA. jonathan.roth@amylin.com
authors.forename: J D
authors.initials: JD
authors.lastname: Roth
authors.forename: L
authors.initials: L
authors.lastname: D'Souza
authors.forename: P S
authors.initials: PS
authors.lastname: Griffin
authors.forename: J
authors.initials: J
authors.lastname: Athanacio
authors.forename: J L
authors.initials: JL
authors.lastname: Trevaskis
authors.forename: R
authors.initials: R
authors.lastname: Nazarbaghi
authors.forename: C
authors.initials: C
authors.lastname: Jodka
authors.forename: J
authors.initials: J
authors.lastname: Athanacio
authors.forename: J
authors.initials: J
authors.lastname: Hoyt
authors.forename: B
authors.initials: B
authors.lastname: Forood
authors.forename: D G
authors.initials: DG
authors.lastname: Parkes
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight; D004195:Disease Models, Animal; D004347:Drug Interactions; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D055786:Gene Knockout Techniques; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000172:deficiency*
chemical_list: D019440:Anti-Obesity Agents; D058228:Islet Amyloid Polypeptide; D044105:Receptor, Melanocortin, Type 4