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Hypertension and obesity

Researchers discover pathway causing hypertension in mice with obesity

The researchers said their work revolves around leptin, a molecule that controls appetite and metabolism in response to food

In a study of mice, Johns Hopkins researchers have revealed exactly which molecules are likely responsible for the link between obesity and hypertension, and that blocking one of these molecules - a signalling channel that's found in a tiny organ on the side of your neck - effectively lowers hypertension in obese mice.

"Obesity leads to a lot of bad cardiovascular outcomes, and a significant portion of those are related to poorly controlled hypertension," said Dr Vsevolod Polotsky, professor of medicine at the Johns Hopkins University School of Medicine and a senior author of the new paper. "We've identified what may be a new way to lower hypertension in obese patients and improve these outcomes."

Reporting their research in the journal Circulation Research, the researchers said their work revolves around leptin, a molecule that controls appetite and metabolism in response to food. Obese people often become resistant to leptin, so rising levels of the molecule after a meal no longer boost metabolism or cause a feeling of fullness. In response to this resistance, leptin levels continue to rise with obesity. Leptin has also been shown to increase hypertension and, surprisingly, obesity does not change that link even when people are resistant to leptin's effects on metabolism and appetite, their hypertension rises in response to the molecule. Until now, researchers were not sure why.

"It didn't make a lot of sense why obese people were only resistant to some of the effects of leptin," added Polotsky. "It suggested to us that maybe leptin was having a peripheral effect outside the brain."

Previous studies had revealed that there were high levels of leptin receptors in the carotid bodies, tiny clusters of cells along the carotid arteries on either side of the throat that respond to changing levels of oxygen and carbon dioxide in the blood. Polotsky wondered whether this could be where leptin affects hypertension, completely separate from its effects on appetite and metabolism in the brain.

Polotsky's group first confirmed that giving high doses of leptin to lean mice triggered a rise in hypertension of 10.5 to 12.2mmHg, while having no effect on heart rate or food intake. Then, they repeated the experiment in mice without functioning carotid bodies. This time, the animals' hypertension did not change in response to leptin. Next, the team studied obese mice that had no leptin receptors and, despite their weight, they had normal hypertension. However, when the researchers injected the genes for leptin receptors directly into the carotid bodies of these mice, the animals' hypertension readings rose by 9.4 to 12.5mmHg.

"This is a completely new mechanism of hypertension in obesity," explained Polotsky.

After establishing that the carotid body is required for leptin to cause hypertension, the researchers wanted to know what other signalling molecules in the carotid body might be involved. By sifting through previously collected data on what molecules are in the carotid body, they identified the transient receptor potential (TRPM7) calcium channel. Polotsky and his team treated mice with the multiple sclerosis drug FTY720 (fingolimod), which blocks channels typically involved in the immune system, including TRPM7 (the drug's mechanism to treat multiple sclerosis is due to blocking a receptor called S1PR1).

In this current study, the drug effectively stopped extra doses of leptin from increasing hypertension in lean mice, both when given systemically and when applied as a topical gel on the skin directly above the carotid bodies.

"We are now working with biochemists to develop a long-acting drug that acts specifically on TRPM7 in the carotid body," concluded Polotsky. More research is needed to determine whether such a drug could effectively treat hypertension in obese people.

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