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Most people know that obese individuals tend to have high blood pressure, but now British researchers have identified the molecular pathway that could explain that link.
In findings published in the Dec. 17 online issue of the New England Journal of Medicine, Sadaf Farooqi, of the University of Cambridge, and her colleagues demonstrated that signaling through the melanocortin-4 receptor (MC4R) helps to regulate blood pressure in humans.
Farooqi and her team studied blood pressure in 46 obese individuals who were missing one copy of the MC4R gene, and compared them to 30 obese individuals who had two normal copies of the gene. Individuals in the MC4R-deficient population tended to have slightly lower blood pressure values than did the control group (123/73 vs. 131/79), and less hypertension overall.
"The people where the MC4R gene is not working correctly actually were protected from high blood pressure," Farooqi explained.
As it turns out, these individuals appeared to have what Farooqi called "impaired sympathetic tone," which is that automatic part of the nervous system that controls the so-called "fight or flight" response to stress, and which apparently mediates this protective effect.
One aspect of the autonomic nervous system, for instance, involves the increase in heart rate that accompanies waking. In both study populations, the heart rate while sleeping was identical and increased upon waking. But the size of the increase in the two groups differed, with MC4R-deficient individuals' heart rate increasing less than control individuals.
Next, Farooqi teamed up with scientists at Eli Lilly, the pharmaceutical company, to test an MC4R agonist -- an experimental compound that works by inducing signaling through the MC4R receptor. The drug is in development as a potential anti-obesity medication, though this study was not assessing its effect on weight loss. Instead, the team looked at the drug's effect on blood pressure in 28 obese individuals (none of whom were MC4R-deficient).
What they observed was an acute, dose-dependent increase in blood pressure upon drug treatment, Farooqi said. "So, basically what this means is that both our own data on the patients with the MC4R gene problem, and the data from Lilly giving the drug, show that this gene is important in controlling blood pressure."
Most people, of course, are not missing the MC4R gene. What normally happens in obese individuals, Farooqi explained, is this: "As people gain weight, they make more fat. And your fat produces a hormone called leptin, and levels of leptin then increase. Leptin then circulates in the bloodstream and goes to the brain, where it triggers MC4R, which then triggers the sympathetic system, and drives up your blood pressure."
Dr. Daniel Marks, of the Oregon Health & Science University in Portland, said, "It is a well-done study and teaches us something about the fundamental physiology of blood pressure regulation in humans."
Yet Marks also cautioned that MC4R is not likely the only link between obesity and blood pressure.
"There's a difference between being statistically significant and clinically significant," he said. "Those are two different issues, and I think the issue of clinical significance is still pretty unknown here."
Dr. George Bakris, of the University of Chicago Pritzker School of Medicine, called the study a "really big deal."
"I think this paper is going to become a real classic," Bakris said, "because it is the first time this kind of characterization has been done in such a very clean way and provides a way of identifying people who may not have a blood pressure problem, even though they may have a weight problem."
Bakris suggested that MC4R antagonists -- drugs that work by blocking MC4R -- could find use as anti-hypertensive medications.
"I personally think that's the most important part of this paper," Bakris said, "is if you prolong the inhibition, you reduce sympathetic tone, blood pressure will go down, and if you don't have any side effects associated with it, that would be huge."
MC4R, Marks explained, is one of five melanocortin receptors in the brain; these proteins regulate skin coloration and stress, among other things. But MC4R regulates body weight, "and it does that by altering both appetite and energetics of your body -- your basal metabolic rate," at least partly via the sympathetic nervous system.
MC4R deficiency is the most common genetic disorder causing obesity, Farooqi said; it accounts for 6 percent of individuals with early-onset obesity and 2.5 percent of obese adults.