Role of hypothalamic melanocortin 3/4-receptors in mediating chronic cardiovascular, renal, and metabolic actions of leptin.
The present study examined whether blockade of melanocortin receptors subtypes 3 and 4 (MC3/4-R) inhibits chronic cardiovascular and dietary responses to leptin infusion. A cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic intracerebroventricular (ICV) infusion via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and IV infusions. After a 5-day control period, rats received (1) 0.9% saline vehicle ICV for 12 days plus leptin (1 microg/kg per minute IV, n=5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 microg/kg per minute IV, n=6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n=8) for 12 days. Leptin infusion in vehicle-treated rats caused a small increase in MAP (5+/-1 mm Hg) despite reduced food intake (23+/-1 to 10+/-1 g/d) and decreased body weight (-6%+/-1%). SHU-9119 infusion completely prevented the cardiovascular and dietary actions of leptin, leading to increased food intake (23+/-1 to 49+/-4 g/d) and body weight (+30%+/-2%), markedly decreased HR (-77+/-9 bpm), and caused a decrease in MAP (-6+/-1 mm Hg). Similar results were observed when SHU-9119 was infused alone in vehicle-treated rats. Leptin decreased plasma insulin to 30% of control values, an effect that was also abolished by SHU-9119 treatment, which caused a 5-fold increase in plasma insulin concentration. Thus, MC3/4-R antagonism completely blocked the chronic cardiovascular, satiety, and metabolic effects of leptin, suggesting that the hypothalamic melanocortin system plays an important role in mediating these actions of leptin.
da Silva
Alexandre A
AA
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-450, USA. asilva@physiology.umsmed.edu
Kuo
Jay J
JJ
Hall
John E
JE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D015918:Infusion Pumps, Implantable; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012083:Renin / Q000097:blood; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
D007328:Insulin; D020738:Leptin; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D012083:Renin