Diminished brain response to nutrients observed in people with obesity

A new study reveals a diminished response to nutrients among people with obesity — and that this brain response is not recovered after weight loss.
An overweight woman and a healthy weight woman with fruits and vegetables.

Illustration from generative AI images (Michael S. Helfenbein)

After a person eats, the gut dispatches a series of signals to the brain conveying the presence of nutrients, a phenomenon that scientists believe may help regulate eating behavior. However, in a new study led by Yale’s Mireille Serlie, researchers found that while the detection of nutrients in the stomach does induce brain activity changes in lean people, such brain responses are largely diminished in people with obesity.

These differences in brain activity, the researchers say, could help explain why it’s difficult for some to lose weight and maintain weight loss.

The findings were published June 12 in Nature Metabolism.

Over 4 million people die each year around the world as a result of being overweight, according to the World Health Organization, and understanding the biological factors that contribute to obesity will be essential for addressing its devastating, global impact, say researchers. And while the ways that the body responds to nutrient intake may be a key factor in eating behavior, the role of nutrient signaling in humans is not well understood.

For the new study, researchers infused glucose or fat directly into the stomach of 28 people identified as “lean” — those with a body mass index (BMI) of 25 or less — and 30 people with obesity (BMI of 30 or higher). They then assessed brain activity though functional magnetic resonance imaging (fMRI).

Among lean participants, the researchers saw evidence of reduced activity across various regions of the brain following the infusion of both glucose and fat. Conversely, they observed no changes in activity in participants with obesity.

This was surprising,” said Serlie, a professor of medicine (endocrinology) at Yale School of Medicine and senior author of the study. “We thought there would be different responses between lean people and people with obesity, but we didn’t expect this lack of changes in brain activity in people with obesity.”

Serlie and her colleagues then took a closer look at a brain region called the striatum, which previous research has shown mediates the rewarding and motivational aspects of food intake and plays a key role in regulating eating behavior. The striatum does this in part through the neurotransmitter dopamine.

Using fMRI, they found that in lean people, both glucose and fat led to decreased activity in two parts of the striatum. However, only glucose led to changes in brain activity in participants with obesity, and only in one area of the striatum. Fat did not change brain activity in this region. When researchers evaluated dopamine release in the striatum following nutrient infusion, they found that glucose induced dopamine release in both groups of participants while fat only caused dopamine release in lean participants.

These findings, the researchers said, are compatible with reduced nutrient sensing in people with obesity.

For the study, participants with obesity then underwent a 12-week dietary weight-loss program; those who lost at least 10% of their body weight were then re-imaged.

For these individuals, the researchers found, weight loss did nothing to change the brain’s response to nutrient infusion. “None of the diminished responses were recovered,” said Serlie.

Prior analyses have found that most people who lose weight regain it within a few years of dieting. These new findings, the researchers say, may help explain why that’s so often the case.

In my clinic, when I see people with obesity, they often tell me, ‘I ate dinner. I know I did. But it doesn’t feel like it,’” said Serlie. “And I think that’s part of this defective nutrient sensing. This may be why people overeat despite the fact that they’ve consumed enough calories. And, importantly, it might explain why it’s so hard to keep weight off.”

Understanding the biology of eating behavior in humans is still in its early stages, says Serlie, and more research will be needed to uncover why diminished nutrient sensing occurs in some people, what biological pathways are involved, and when these changes begin to take hold.

Everyone overeats at times. But it’s unclear why some people continue to overeat and others don’t,” she said. “We need to find where that point is when the brain starts to lose its capacity to regulate food intake and what determines that switch. Because if you know when and how it happens, you might be able to prevent it.”

Similarly, knowing when changes to nutrient-sensing become irreversible would help physicians determine treatment paths for patients. And one goal for the future, Serlie said, would be to find a way to restore nutrient sensing, if possible.

Regardless, she said, the findings drive home the human brain’s key role in obesity.

People still think obesity is caused by a lack of willpower,” said Serlie. “But we’ve shown that there is a real difference in the brain when it comes to nutrient sensing.”

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Media Contact

Fred Mamoun: fred.mamoun@yale.edu, 203-436-2643