Obesity seems to alter the normal way the brain responds to sugar and fat — a problem that may not be corrected by weight loss, a new study suggests.

“It could help explain why weight loss and weight-loss maintenance are so hard,” said senior researcher Dr. Mireille Serlie, a professor at Yale School of Medicine.

She and her colleagues found that compared with lean adults, those with obesity did not have the same brain responses to infusions of dietary fat or sugar into the stomach. Their brain activity was blunted, and they did not have the normal release of dopamine — a chemical involved in feelings of “reward” from food.

“Our interpretation is, there’s a generally reduced nutrient-sensing in people with obesity,” said Serlie.

In essence, she said, the brain “was not aligned with what was happening in the gut.”

And unfortunately, the study found, that disconnect was not restored when study participants went on a reduced-calorie diet for three months and shed 10% of their starting weight.

That does not necessarily mean the brain differences are permanent, according to Serlie. It’s possible that with more time and sustained weight loss, people would regain their nutrient sensing.

But even if an improvement is merely delayed, that’s still significant.

Research in lab animals has shown that the brain not only responds to the taste and smell of food, but also has specific responses to the presence of nutrients in the gut — independent of the sensory experiences of eating.

“The leap forward in this study is that they’re showing this is happening in humans, too, but the response is completely blunted in people with obesity,” said Alexandra DiFeliceantonio, a neuroscientist at Virginia Tech’s Fralin Biomedical Research Institute, in Roanoke, Va.

She is co-author of a commentary published with the study June 12 in the journal Nature Metabolism.

According to DiFeliceantonio, nutrient signaling between the gut and the brain may be important in what people choose to eat. The new findings, she said, suggest that system is “broken in some way” in the presence of obesity.

A basic take-home message, both researchers said, is that lasting weight loss is not about “willpower.”

People have to deal with not only the external obstacles — like being surrounded by cheap, readily available junk food — but a physiology that makes diet changes and weight loss tougher.

“We call it the hungry brain,” Serlie said.

For the study, she and her colleagues recruited 30 adults with a healthy body weight and 30 with obesity. First, they used brain imaging to analyze the participants’ responses to infusions of glucose (sugar) and lipids (fat). The nutrients were delivered directly to the stomach, to capture the brain’s response to the nutrients — not the taste and smell of food.

Among the lean participants, the researchers found, the nutrients triggered specific patterns of brain activity that were “severely impaired” in those with obesity. The latter group also showed a lesser release of dopamine from an area of the brain called the striatum, which helps regulate people’s eating behavior.

Next, the participants with obesity started a three-month weight-loss program, cutting calories with the goal of losing 10% of their starting weight. On average, they did achieve that — but their gut-brain nutrient signaling was not improved.

The findings are just a beginning, Serlie said, and there are plenty of questions ahead.

The researchers do think that the blunted nutrient signaling is a consequence of obesity, rather than a cause. But it’s not clear when exactly the signaling becomes impaired, Serlie said, or precisely how.

“We want to understand what pathways in the brain are involved in this maladaptation,” she said.

With that greater understanding, DiFeliceantonio said, it may become possible to improve impaired nutrient signaling — whether that’s through diet and lifestyle, a medication or some other treatment.

However, no one is saying that a pill targeting nutrient signaling will be the magic bullet.

If anything, both researchers said, the new findings demonstrate the complexity of obesity and the gut-brain communication highway.

“It’s way more complex than we could’ve imagined,” DiFeliceantonio said.

Hopefully, she added, this type of research will help reduce the stigma surrounding obesity and weight loss.

Serlie made a similar point. “I do think people get blamed,” she said.

But, Serlie added, “this is not about willpower. It’s a real struggle. And we’re starting to understand why people struggle.”

More information

The U.S. National Institutes of Health has more on managing obesity.

SOURCES: Mireille Serlie, MD, PhD, professor, medicine (endocrinology), Yale School of Medicine, New Haven, Conn.; Alexandra DiFeliceantonio, PhD, assistant professor, Fralin Biomedical Research Institute at VTC, Roanoke, Va.; Nature Metabolism, June 12, 2023, online

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