A common calorie-free sweetener alters brain activity and appetite control, new research suggests

Consuming sucralose, a widely used non-caloric sweetener, may influence how the brain regulates hunger and body weight. A new study published in Nature Metabolism found that sucralose increases activity in the hypothalamus—a key brain region involved in appetite regulation—compared to caloric sugar (sucrose) and water. The findings suggest that even though sucralose lacks calories, it can trigger neural responses linked to increased hunger and alter the way the brain communicates with areas involved in motivation and sensory processing.

Sucralose is a popular sugar substitute used in many diet sodas, baked goods, and low-calorie snacks. It provides a sweet taste without adding calories, which makes it attractive for people trying to lose weight or control blood sugar. However, while it may reduce calorie intake in the short term, its effects on appetite and metabolism are not fully understood. Some researchers have speculated that sucralose might confuse the brain’s hunger-regulating circuits by delivering sweetness without the expected nutrients that usually follow sugar intake. This mismatch may disrupt normal appetite control and possibly promote overeating.

To investigate these effects, researchers at the University of Southern California conducted a randomized crossover trial involving 75 young adults between the ages of 18 and 35. The participants included individuals with healthy weight, overweight, and obesity. Each participant attended three separate sessions during which they consumed one of three drinks: a sucralose-sweetened beverage, a sucrose-sweetened beverage with the same level of sweetness, or water as a control. The sessions were spaced at least two days apart, and the order of drinks was randomized and blinded to both participants and experimenters.

Before and after each drink, the researchers used functional MRI to measure blood flow in the hypothalamus and assess brain activity. Increases in hypothalamic blood flow are associated with hunger, while reductions typically occur after eating and are linked to satiety. In addition to brain imaging, researchers collected blood samples to measure glucose, insulin, and GLP-1 (a hormone involved in satiety), and they asked participants to rate their hunger at multiple time points.

The results showed that consuming sucralose, compared to sucrose and water, increased blood flow in the lateral hypothalamus. This region is known to be involved in triggering hunger and motivating food-seeking behavior. Notably, sucralose consumption also increased self-reported hunger levels compared to sucrose, despite containing no calories. In contrast, sucrose consumption led to increases in blood glucose and decreases in medial hypothalamic blood flow—responses typically associated with feelings of fullness.

Brain imaging also revealed that sucralose altered the functional connectivity between the hypothalamus and other brain regions. For example, after drinking sucralose, participants showed stronger connections between the hypothalamus and areas involved in motivation (like the anterior cingulate cortex) and body awareness (such as the parietal lobule). These changes suggest that sucralose may heighten the brain’s responsiveness to food cues or amplify motivational signals related to eating.

Interestingly, the effects of sucralose varied by body weight and sex. Among participants with healthy weight, sucralose triggered greater hypothalamic activation compared to sucrose, while individuals with obesity showed stronger responses to sucralose compared to water. Those who were overweight fell somewhere in between. Additionally, women showed stronger brain responses to sucralose than men, consistent with previous research suggesting sex differences in sensitivity to food cues and sweet taste.

While the sucrose drink caused measurable increases in glucose, insulin, and GLP-1, sucralose did not. Importantly, the drop in medial hypothalamic blood flow after sucrose ingestion was associated with increased glucose levels and reduced hunger, reinforcing the idea that nutrient signals—especially glucose—help suppress appetite via hypothalamic pathways. These relationships were not seen after sucralose consumption, which did not raise glucose or suppress hypothalamic activity in the same way.

The researchers also explored how individual differences in insulin sensitivity affected brain responses. Participants with lower insulin sensitivity, a marker of metabolic dysfunction, showed greater hypothalamic responses to sucralose than those with higher insulin sensitivity. This finding suggests that people with impaired metabolic function may be more sensitive to the appetite-related effects of non-caloric sweeteners, although more research is needed to confirm this link.

Taken together, the study highlights a paradox: sucralose does not provide calories, but it can stimulate the brain in ways that resemble hunger. The sweet taste, uncoupled from the expected metabolic signals that typically accompany caloric intake, appears to disrupt normal appetite signaling in the hypothalamus. Over time, this could potentially lead to increased food consumption or altered eating patterns, although the study only examined short-term effects.

According to Kathleen Alanna Page, the study’s senior author and director of the USC Diabetes and Obesity Research Institute, these findings raise new questions about the widespread use of artificial sweeteners. “Are these substances actually helpful for regulating body weight? What happens in the body and brain when we consume them, and do the effects differ from one person to the next?” she asked.

While the study provides evidence about how sucralose affects the brain, it also has some limitations. The researchers focused on short-term responses to single doses of sucralose under controlled conditions. Long-term studies are needed to determine whether repeated exposure to non-caloric sweeteners leads to sustained changes in appetite, eating behavior, or body weight. In addition, although the study matched drinks for sweetness intensity, it did not measure participants’ subjective experience of sweet taste or their preferences, which could influence brain responses.

The researchers also noted that their participant group consisted of young, healthy adults who were not trying to lose weight. Results might differ in older adults, individuals with diabetes, or those actively managing their weight. The study also focused only on sucralose, leaving open the question of whether other sweeteners—such as aspartame, saccharin, or stevia—have similar or different effects on the brain and appetite regulation.

To address some of these gaps, Page and her team have launched a follow-up study examining how non-caloric sweeteners affect brain development and appetite regulation in children and adolescents, who are among the heaviest consumers of sugar substitutes. “The brain is vulnerable during this time,” Page explained, “so it could be a critical opportunity to intervene.”

The study, “Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights,” was authored 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.