The elusive link between obesity and high blood pressure has been pinned down to the action of leptin in the brain, and we might be able to block it with drugs.

We’ve known for more than 30 years that fat and high blood pressure are linked, but finding what ties them together has been difficult. One of the favourite candidates has been leptin – a hormone produced by fat cells.

Under normal circumstances, when fat cells produce leptin, the hormone sends the message that you’ve had enough food. But in people with obesity, the body stops responding to this message, and large levels of leptin build up.

Leptin is known to activate the regulatory network called the sympathetic nervous system, and it’s the activation of sympathetic nerves on the kidneys that seem to be responsible for raising blood pressure. Leptin has thus been linked to blood pressure. However, conclusive evidence has been hard to come by.


No leptin, no problem

Michael Cowley of Monash University in Melbourne, Australia, and his colleagues have now conducted a string of experiments that provide some evidence. Through genetic and drug experiments in mice, they have pinpointed an area in the mouse brain that increases blood pressure when it is exposed to high leptin levels.

This region is called the dorsomedial hypothalamus, and is thought to be involved in controlling energy consumption. Their findings show that high levels in leptin do indeed boost blood pressure, via this brain region.

The team then looked at people who either couldn’t produce leptin or couldn’t respond to leptin. In both those groups, being obese did not lead to high blood pressure – suggesting that leptin was a crucial linking factor.

Cowley says it used to be thought that leptin specifically activated the sympathetic nervous system connected to brown fat, which can directly burn energy. “But it also spills over into activation of the sympathetic nervous system of the heart and the kidney,” says Cowley. “And so it’s sort of a cruel twist of fate that as the brain tries to help you lose weight, it increases heart rate and blood pressure.”

“It really is an impressive piece of work,” says David Grattan from the University of Otago in New Zealand. “The animal data are extremely strong and the human data are consistent,” he says.

But Murray Esler from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, says he’s still not convinced that leptin does regulate blood pressure in humans. “If you administer leptin to obese people for a year or two, it never puts up their blood pressure,” he says. “And we’ve looked for a connection between the sympathetic nerves firing in the kidney and increased leptin and no relationship exists.”

However Grattan says that when researchers give people leptin in studies, it’s often associated with weight-loss, which could cause blood pressure to drop, counteracting blood-pressure rise from the hormone.

Ravenously hungry

Cowley says the chemical his team has used in the mice to block leptin, or one like it, might work in humans, but it’s not a promising treatment – it would probably also make people ravenously hungry. Instead, his team might need to narrow down the pathway between leptin and the sympathetic nervous system and try to block some component of that instead.

But Cowley thinks just having the knowledge of how obesity leads to heart disease will help patients directly. “For the first time the conversation is not ‘you need to lose weight because being obese increases your risk of heart disease’,” he says. “Now it’s ‘there’s a hormone secreted by your fat that causes heart disease. Having a conversation about increased risk is nowhere near as persuasive as one about the direct cause.”

“I think that might have a bigger clinical impact that the potential therapeutic development,” he says.

Journal reference: Cell, DOI: 10.1016/j.cell.2014.10.058