How fatty diets stop the brain from saying 'no' to food

People with obesity often encounter difficulties when it comes to regulating their eating habits, since their bodies no longer know when they are and are not hungry. Researchers ask why this happens.

How do we know when to eat, and when to stop eating? Easy: we feel hungry, so we know it's time for a meal.

Then, when we feel full, we know it's time to put down the cutlery and get on with our day.

These states of hunger and satiety occur due to the brain's ability to "decode" the signals of two key hormones: the so-called "hunger hormone," ghrelin, and the "energy expenditure hormone," leptin, which is released when it's time to stop eating and start burning those calories.

Obesity, researchers point out, is frequently characterized by leptin resistance, which means that the body is unable to "read" the signals sent by the hormone that typically curbs appetite.

What remains unclear is how leptin resistance develops, and which elements in the leptin-brain circuitry are affected.

A new study from the University of California, San Diego and a number of international research institutions has revealed that high-fat diets may impair the brain's capacity to "sense" leptin, therefore leading to leptin resistance.

The researchers have published their findings in the journal Science Translational Medicine.

The enzyme that damages leptin receptors

"Our hypothesis," says first study author Rafi Mazor, "was that an enzyme breaking down proteins into amino acids and polypeptides can cleave membrane receptors and lead to dysfunctional activity."

That is, the researchers wanted to test whether, in the process of metabolizing the fatty foods, the body creates a type of molecule that "cuts off" the leptin receptors found on the neuronal cells in the hypothalamus, which is the region of the brain that typically receives the leptin signals.

They tested this hypothesis in a mouse model of obesity in which the animals were regularly fed a high-fat diet.

Indeed, Mazor and colleagues found that their premise had been correct. The brains of mice that had eaten a fatty diet produced a protease — a type of enzyme — called "metalloproteinase-2" (Mmp-2).

Activated Mmp-2 then cuts the leptin receptors found on the membranes of neuronal cells in the hypotalamus, thereby impairing the brain's ability to tell when it is time to stop eating.

The scientists were able to identify Mmp-2 and confirm its impact on leptin receptors by assessing protease activity in the brains of mice with obesity. By looking at the response of leptin receptors, they noticed that Mmp-2 activity was preventing them from binding to leptin.

Moreover, in laboratory cultures of brain cells with leptin receptors, Mazor and team observed the same effect: Mmp-2 exposure impaired the cells' response to the hormone.

Conversely, when the research team engineered a group of mice not to produce Mmp-2, the animals did not gain much extra weight — even when they ate a fatty diet — and the leptin receptors in their brains remained intact.

'A new field of study for metabolic disease'

By observing this mechanism at play, the researchers have also started to develop a strategy that, they hope, would be able to block it. Therefore, they ask whether using Mmp-2 inhibitors could counteract leptin resistance and help individuals shed extra weight.

"When you block the protease that leads to the receptors not signaling, you can treat the issue," believes study co-author Prof. Geert Schmid-Schönbein.

The scientists aim to eventually develop such an inhibitor themselves; in the meantime, they are planning to conduct a study with human participants, so as to verify whether the same leptin-blocking mechanism applies.

"In the future," Mazor adds, "we will try to find out why proteases are activated, what is activating them, and how to stop it," adding, "There is still a lot of work to do to better understand receptor cleaving and the loss of cell function while on a high-fat diet."

"We opened a new field of study for metabolic disease. We need to ask what other pathways, in addition to leptin and its receptors, undergo a similar destructive process and what the consequences might be."

Rafi Mazor