FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 360:44-52 January 1, 2009 Number 1 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans.

Methods We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.

Results The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (±SE) systolic blood pressures of 123±14 mm Hg and 131±12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73±10 mm Hg and 79±7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3±1.9 mm Hg in systolic blood pressure and of 6.6±1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.

Conclusions Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.

Source Information

From the University of Cambridge Metabolic Research Laboratories (J.R.G., J.M.K., E.H., S.O., I.S.F.) and Medical Research Council Epidemiology Unit (S.B.), the Institute of Metabolic Science and the Department of Radiology (T.C.S., D.J.L.), Addenbrooke's Hospital, Cambridge, United Kingdom; Eli Lilly, Lilly Corporate Center, Indianapolis (J.W.M., J.H.S., G.S.C., J.P.M.); and Biotrial, Rennes, France (B.A.).

This article (10.1056/NEJMoa0803085) was published at NEJM.org on December 17, 2008.

Address reprint requests to Dr. Farooqi at the Institute of Metabolic Science, Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Rd., Box 289, Cambridge CB2 0QQ, United Kingdom, or at isf20{at}cam.ac.uk.

Full Text of this Article

This article has been cited by other articles:

• Kennedy, A. J., Ellacott, K. L. J., King, V. L., Hasty, A. H. (2010). Mouse models of the metabolic syndrome. DMM 3: 156-166 [Abstract] [Full Text]  
• Maier, T., Hoyer, J. (2010). Modulation of blood pressure by central melanocortinergic pathways. Nephrol Dial Transplant 25: 674-677 [Full Text]  
• Skibicka, K. P., Grill, H. J. (2009). Hypothalamic and Hindbrain Melanocortin Receptors Contribute to the Feeding, Thermogenic, and Cardiovascular Action of Melanocortins. Endocrinology 150: 5351-5361 [Abstract] [Full Text]  
• Corander, M. P., Fenech, M., Coll, A. P. (2009). Science of Self-Preservation: How Melanocortin Action in the Brain Modulates Body Weight, Blood Pressure, and Ischemic Damage. Circulation 120: 2260-2268 [Full Text]  
• Grassi, G. (2009). Assessment of Sympathetic Cardiovascular Drive in Human Hypertension: Achievements and Perspectives. Hypertension 54: 690-697 [Abstract] [Full Text]  
• Morley, J. E., Sinclair, A. (2009). The metabolic syndrome in older persons: a loosely defined constellation of symptoms or a distinct entity?. Age Ageing 38: 494-497 [Full Text]  
• Mark, A. L. (2009). Cardiovascular Side Effects of Antiobesity Drugs: A Yellow Flag in the Race to Safe Pharmacotherapy for Obesity. Circulation 120: 719-721 [Full Text]  
• Balthasar, N. (2009). Feeding signals to the hungry mind. Exp Physiol 94: 857-866 [Abstract] [Full Text]  
• Timpson, N. J., Harbord, R., Davey Smith, G., Zacho, J., Tybjaerg-Hansen, A., Nordestgaard, B. G. (2009). Does Greater Adiposity Increase Blood Pressure and Hypertension Risk?: Mendelian Randomization Using the FTO/MC4R Genotype. Hypertension 54: 84-90 [Abstract] [Full Text]  
• Mohan, C., Agarwal, A. K. (2009). Melanocortin-4-Receptor Autoantibodies: A New Player in Obesity. J. Clin. Endocrinol. Metab. 94: 757-759 [Full Text]