Abstract | AIMS: 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.
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Authors | J D Roth, L D'Souza, P S Griffin, J Athanacio, J L Trevaskis, R Nazarbaghi, C Jodka, J Athanacio, J Hoyt, B Forood, D G Parkes |
Journal | Diabetes, obesity & metabolism
(Diabetes Obes Metab)
Vol. 14
Issue 7
Pg. 608-15
(Jul 2012)
ISSN: 1463-1326 [Electronic] England |
PMID | 22276636
(Publication Type: Journal Article)
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Copyright | © 2012 Blackwell Publishing Ltd. |
Chemical References |
- Anti-Obesity Agents
- Islet Amyloid Polypeptide
- Receptor, Melanocortin, Type 4
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Topics |
- Animals
- Anti-Obesity Agents
(pharmacology)
- Body Weight
- Disease Models, Animal
- Drug Interactions
- Eating
- Energy Metabolism
- Female
- Gene Knockout Techniques
- Islet Amyloid Polypeptide
(administration & dosage, deficiency, pharmacology)
- Male
- Mice
- Obesity
(drug therapy)
- Rats
- Rats, Sprague-Dawley
- Receptor, Melanocortin, Type 4
(agonists, deficiency)
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