A new USC study reveals that sucralose, a popular artificial sweetener, may trick the brain by triggering hunger-related activity in the hypothalamus without delivering the expected calories.
Unlike sugar, sucralose fails to activate hormones that promote fullness and alters how brain regions involved in motivation and sensory processing communicate. The effects were strongest in people with obesity and were more pronounced in women. These findings raise questions about how calorie-free sweeteners might influence long-term eating habits, and even brain development in children.
Sucralose Sparks Brain Activity Linked to Hunger
Consuming sucralose, a common calorie-free sugar substitute, activates the hypothalamus, a part of the brain that helps regulate appetite and body weight, more than regular sugar does, according to a new study from USC. The research also found that sucralose changes how the hypothalamus interacts with other brain areas, including those involved in motivation. These findings were recently published in Nature Metabolism.
Roughly 40% of Americans use sugar substitutes, often to cut calories or manage sugar intake. But do these sweeteners actually help with weight control? And how do they affect the body and brain across different individuals? Those were the key questions driving the research, said Kathleen Alanna Page, MD, director of the USC Diabetes and Obesity Research Institute and co-chief of the Division of Endocrinology and Diabetes at the Keck School of Medicine.
Testing the Brain’s Sweet Response
To explore this, Page and her team conducted a randomized study to measure how sucralose influences brain activity, hormone levels, and feelings of hunger. While past studies, mainly in animals or based on population data, have suggested a link between artificial sweeteners and obesity, few have directly tested how these sweeteners impact hunger in humans.
With funding from the National Institutes of Health, the researchers tested how 75 participants responded after consuming water, a drink sweetened with sucralose or a drink sweetened with regular sugar. They collected functional magnetic resonance imaging (fMRI) 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.
Sucralose Confuses the Brain’s Signals
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 behavior down the line.
“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.
Inside the Brain’s Hunger Network
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.
Sweetener Alters Brain Connectivity
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.”
Gender Differences and Future Questions
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.
Reference: “Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights” by Sandhya P. Chakravartti, Kay Jann, Ralf Veit, Hanyang Liu, Alexandra G. Yunker, Brendan Angelo, John R. Monterosso, Anny H. Xiang, Stephanie Kullmann and Kathleen A. Page, 26 March 2025, Nature Metabolism.
DOI: 10.1038/s42255-025-01227-8
In addition to Page, the study’s other authors are Sandhya P. Chakravartti, Hanyang Liu, Alexandra G. Yunker and Brendan Angelo from the Diabetes and Obesity Research Institute and the Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine of USC, University of Southern California; Kay Jann from the Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California; John R. Monterosso from the Department of Psychology, University of Southern California; Anny H. Xiang from the Department of Research and Evaluation, Kaiser Permanent Southern California; and Stephanie Kullmann and Ralf Veit from the Institute for Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany.
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R01DK102794, F31DK137584].
