Abstract-The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (Ϫ/Ϫ) and heterozygous (ϩ/Ϫ) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (nϭ5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (Ϫ/Ϫ) mice were severely obese compared with MC4R (ϩ/Ϫ) and WT mice (body weight 48Ϯ1.5 versus 31Ϯ0.6 and 30Ϯ0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (Ϫ/Ϫ) 110Ϯ3 mm Hg; MC4R (ϩ/Ϫ) 109Ϯ2 mm Hg; WT 114Ϯ2 mm Hg), and HR in MC4R (Ϫ/Ϫ) was lower than in WT (604Ϯ5 versus 645Ϯ9 bpm; PϽ0.05) but not different from MC4R (ϩ/Ϫ) (625Ϯ13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (Ϫ/Ϫ) compared with MC4R (ϩ/Ϫ) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (Ϫ/Ϫ) than in MC4R (ϩ/Ϫ) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (Ϫ/Ϫ) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities. Key Words: obesity Ⅲ insulin resistance Ⅲ hypertension, sodium-dependent Ⅲ arterial pressure Ⅲ renin-angiotensin system E vidence from epidemiological, clinical, and experimental studies has consistently demonstrated that obesity is a major cause of essential hypertension. 1-3 Previous studies show that ␣/␤-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain in diet-induced obese animal models, indicating that increased sympathetic nervous system (SNS) activation is an important cause of obesity-induced hypertension. 3,4 However, the mechanisms that link SNS activation to the development of hypertension in obesity are still unclear.One potential mechanism that could link obesity, SNS activation, and hypertension is the hypothalamic proopiomelanocortin (POMC) pathway. Several studies have indicated that the hypothalamic melanocortin system, acting through the melanocortin-3 receptor (MC3R) and MC4R, is a major regulator of energy balance. ␣-Melanocyte-stimulating hormone (␣-MSH), the proteolytic byproduct of the POMC peptide, activates the hypothalamic MC3/4R to suppress appetite and to increase energy expenditure. 5 Recent studies suggest that the hypothalamic melanocortin system may also be important in cardiovascular regulation. For example, acute intracerebroventricular injections of ␣-MSH increase SNS activity to the kidneys, 6 and chronic activation of MC3/4...

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