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(Hypertension. 2006;47:259.)
© 2006 American Heart Association, Inc.

Original Articles

Does Obesity Induce Resistance to the Long-Term Cardiovascular and Metabolic Actions of Melanocortin 3/4 Receptor Activation?

Alexandre A. da Silva; Jay J. Kuo; Lakshmi S. Tallam; Jiankang Liu; John E. Hall

From the Department of Physiology and Biophysics and Center of Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Miss.

Correspondence to Alexandre A. da Silva, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail asilva{at}physiology.umsmed.edu

Previous studies suggest that blockade of melanocortin 3 and 4 receptors (MC3/4-R) markedly attenuates the chronic hypertensive effects of leptin. Although obesity has been reported to be associated with leptin "resistance," it is unclear whether obesity alters the cardiovascular and metabolic effects of chronic MC3/4-R activation. Therefore, we tested whether the cardiovascular and metabolic actions of MC3/4-R activation are attenuated in Sprague-Dawley rats fed a high-fat diet (HF, n=6) compared with rats fed a standard chow (NF, n=6) for 12 months. A 21G steel cannula was placed in the lateral ventricle for ICV infusion, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) 24 hours/day and IV infusions. After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558±21 versus 485±13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9±0.5 versus 2.7±0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109±3 versus 100±1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7±2 and 6±1 mm Hg), decreased caloric intake (–32±2 and –25 ±2 kcal/day), and reduced insulin levels in both groups by 50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension.

Key Words: diet • blood pressure • insulin resistance • heart rate • glucose • leptin • metabolism • hypertension

This article has been cited by other articles:

				A. A. da Silva, J. M. do Carmo, J. N. Freeman, L. S. Tallam, and J. E. Hall A Functional Melanocortin System May Be Required for Chronic CNS-Mediated Antidiabetic and Cardiovascular Actions of Leptin Diabetes, August 1, 2009; 58(8): 1749 - 1756. [Abstract] [Full Text] [PDF]

				A. A. da Silva, J. M. do Carmo, B. Kanyicska, J. Dubinion, E. Brandon, and J. E. Hall Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats Hypertension, April 1, 2008; 51(4): 884 - 890. [Abstract] [Full Text] [PDF]