Calorie-free sweeteners can disrupt the brain’s appetite signals making people feel hungrier than when they consume sugar-sweetened foods, a study from the University of Southern California has found.

The finding suggests that, rather than helping with calorie reduction, artificial sweeteners may encourage people to overeat.   

In the study, researchers led by Kathleen Alanna Page, designed a randomized experiment to test how the artificial sweetener sucralose changes brain activity, hormone levels and hunger. Earlier research has hinted at a link between calorie-free sweeteners and obesity, but has not directly shown how these substances affect hunger in humans.

The team tested how 75 participants responded after consuming water, a drink sweetened with sucralose or a drink sweetened with regular sugar. To do this they collected brain scans, blood samples and hunger ratings before and after participants consumed the drink. Sucralose increased hunger and activity in the hypothalamus, especially in people with obesity. It also changed the way the hypothalamus communicated with other brain regions. Unlike sugar, sucralose did not increase blood levels of certain hormones that create a feeling of fullness. 

On average, participants who drank water containing sucralose said their appetite increased by nearly 20% compared with drinking water.

The findings show how sucralose confuses the brain by providing a sweet taste without the expected caloric energy, said Page, who is also an associate professor of medicine at the Keck School of Medicine. This “mismatch” could even trigger changes in cravings and eating behaviour down the line, she adds.

“If your body is expecting a calorie because of the sweetness, but doesn’t get the calorie it’s expecting, that could change the way the brain is primed to crave those substances over time,” she said.

An altered brain response
The study included 75 participants, about evenly split between male and female and weight status (healthy weight, overweight or obese). On three separate visits, each participant was tested with sucralose, sugar or water, allowing the researchers to look for differences both within and between individuals.

At each visit, researchers collected baseline brain scans and blood samples. They also asked participants to rate how hungry they were. Next, participants consumed 300 ml of water, a sugar-sweetened drink or a drink sweetened with sucralose. Researchers then collected follow-up brain scans, blood samples and hunger ratings several times during the next two hours.

Compared to drinking sugar, drinking sucralose increased brain activity in the hypothalamus and increased feelings of hunger. Compared to drinking water, sucralose increased hypothalamic activity, but did not change feelings of hunger. Those effects were strongest in people with obesity.

The researchers also used fMRI scans to study functional connectivity, which shows how regions of the brain communicate with one another. Consuming sucralose led to increased connectivity between the hypothalamus and several brain areas involved with motivation and sensory processing—including the anterior cingulate cortex, which plays a role in decision-making. Those findings suggest that sucralose could impact cravings or eating behavior, Page said.

As expected, consuming sugar led to increases in blood sugar and the hormones that regulate it, including insulin and glucagon-like peptide 1 (GLP-1). Drinking sucralose, on the other hand, had no effect on those hormones.

“The body uses these hormones to tell the brain you’ve consumed calories, in order to decrease hunger,” Page said. “Sucralose did not have that effect—and the differences in hormone responses to sucralose compared to sugar were even more pronounced in participants with obesity.”

Age, sex and long-term effects
While the study answers key questions about how the brain and body respond to sucralose, it raises several others. Do the observed changes in brain and hormone activity have long-term effects? Longitudinal studies that measure body weight and eating behavior are needed to help clarify the link.

Page and her colleagues also observed differences by sex: female participants showed greater changes in brain activity than did male participants, suggesting that sucralose may affect the sexes differently.

The researchers have now begun a follow-up study that explores how calorie-free sweeteners affect the brains of children and adolescents, who consume more sugar and sugar substitutes than any other age group.

“Are these substances leading to changes in the developing brains of children who are at risk for obesity? The brain is vulnerable during this time, so it could be a critical opportunity to intervene,” Page said.