Published Online
on May 3, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on January 13, 2004
Revised on February 17, 2004

Role of Hypothalamic Melanocortin 3/4-Receptors in Mediating Chronic Cardiovascular, Renal, and Metabolic Actions of Leptin

Alexandre A. da Silva^*; Jay J. Kuo; and John E. Hall

From the University of Mississippi Medical Center, Jackson.

^* To whom correspondence should be addressed. E-mail: asilva{at}physiology.umsmed.edu.

Abstract--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 µg/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 µg/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.

Key words: hypertension • blood pressure • obesity • insulin

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