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Table of Contents
In a nutshell
- The artificial sweetener sucralose may increase activity in the brain’s hunger-regulating center (hypothalamus) compared to regular sugar, potentially stimulating appetite instead of satisfying it.
- The brain response to the artificial sweetener varies by body weight and sex, with stronger effects observed in people with obesity and in female participants.
- Sucralose may create a “mismatch” in the brain by providing sweet taste without delivering the expected calories, which may alter functional connections between brain regions involved in hunger, motivation, and reward processing.
LOS ANGELES — Most of us reach for diet sodas and sugar-free treats with the best intentions – to satisfy our cravings without the caloric consequences. But what if some artificial sweeteners –the very products designed to help us manage our weight — are actually sending confusing signals to our brains? New research suggests that the sugar substitute sucralose could be doing just that.
Published in Nature Metabolism by researchers from the University of Southern California, the study uncovers concerning evidence that sucralose – one of the most widely used artificial sweeteners – may interfere with the brain’s natural hunger regulation mechanisms in ways that could potentially increase appetite rather than satisfy it.
The research reveals how the brain responds differently to artificial sweeteners compared to regular sugar, potentially creating a disconnect between the sweet taste our tongues experience and the metabolic feedback our brains expect to receive. The findings offer fresh insights into why weight management remains challenging despite widespread use of non-caloric sweeteners.
The research team, led by Dr. Kathleen A. Page, 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 of USC, conducted a randomized crossover trial with 75 young adults across varying weight categories. Their discoveries might make you think twice before reaching for that next diet soda.
Sweet Taste Without the Satisfaction
When we consume something sweet, our brain prepares for the arrival of calories and nutrients. It’s a relationship that evolved over millennia – sweet taste signals energy is coming. But artificial sweeteners could be breaking this natural connection.
In the study, participants consumed drinks containing either sucralose, regular sugar (sucrose), or plain water. Researchers then monitored what happened in their hypothalamus – the brain region responsible for regulating hunger and metabolic processes.
Results show that sucralose stimulated greater hypothalamic blood flow compared to sucrose or water. In the brain’s language, this increased activity is typically associated with hunger, not satisfaction.
More tellingly, participants reported feeling significantly hungrier after drinking the sucralose beverage compared to the sugar-sweetened one. The sugar drink triggered appropriate metabolic responses – raising blood glucose, insulin, and GLP-1 hormone levels – which corresponded with decreased hypothalamic activity and reduced hunger. But sucralose, despite delivering the same sweet taste, failed to provide these metabolic signals.
It appears that the artificial sweetener may create a form of sensory confusion. Your tongue tastes sweetness, but your body never receives the calories it expects. This mismatch might leave the brain in a state of unfulfilled anticipation, potentially driving continued hunger rather than satisfaction.
Different Bodies, Different Responses
Particularly fascinating was how body weight influenced these responses. The study found distinct differences in brain reactions across healthy weight, overweight, and obese individuals.
Those with healthy weight showed greater hypothalamic activation after consuming sucralose compared to sucrose. Meanwhile, individuals with obesity exhibited stronger hypothalamic responses to sucralose versus water, but not versus sucrose.
These findings suggest that weight status might influence how the brain interprets and responds to sucralose, reflecting complex interactions between body composition and brain signaling pathways.
Sex differences emerged as well, with females showing more pronounced hypothalamic responses to sucralose compared to both sugar and water. This aligns with previous research indicating that women may have enhanced brain responses to food cues compared to men.
How Sucralose May Rewire Brain Connections
Beyond just activating the hypothalamus, sucralose also altered the functional connections between brain regions. Compared to sucrose, sucralose increased connectivity between the hypothalamus and the anterior cingulate cortex – an area involved in motivation and reward processing.
When compared to water, sucralose enhanced connections between the hypothalamus and the superior parietal lobule, which plays a role in sensory integration.
These connectivity changes suggest that the artificial sweetener might influence not only our physical hunger signals but also our psychological relationship with food, potentially affecting motivation and pleasure-seeking behaviors around eating.
Another significant finding involved insulin sensitivity – a measure of how effectively the body processes glucose. Participants with lower insulin sensitivity showed stronger hypothalamic responses to sucralose compared to those with higher insulin sensitivity, regardless of their body weight.
This suggests that metabolic health factors beyond just body weight might influence how the brain responds to sucralose. For individuals with insulin resistance or prediabetes, the sugar substitute might trigger even stronger hunger signals in the brain.
Rethinking Our Relationship with Artificial Sweeteners
Since their introduction to the market, artificial sweeteners have been promoted as tools to help reduce sugar consumption while satisfying our innate preference for sweetness. The average American consumes approximately 17 teaspoons of added sugar daily – well above recommended limits – so the appeal of a calorie-free alternative is obvious.
But this research adds to growing concerns that artificial sweeteners might not deliver on their promise of simpler weight management. If these substances are potentially disrupting our brain’s natural appetite regulation mechanisms, the calculation becomes more complex.
The researchers emphasize that their study focused on acute responses to a single exposure of sucralose. More research is needed to understand the long-term effects of regular artificial sweetener consumption and whether the brain eventually adapts to these substances.
Most artificially sweetened products aren’t consumed in isolation but alongside other foods or as part of meals. The researchers note that how artificial sweeteners affect brain signaling when consumed with carbohydrates or proteins warrants further investigation, especially since previous studies have suggested that consuming artificial sweeteners with carbohydrates might alter brain and metabolic responses.
While this study specifically examined sucralose, hundreds of different artificial and natural non-caloric sweeteners exist in the marketplace, each with its own chemical structure and potential physiological effects. Future research will need to explore whether similar brain responses occur with other popular sweeteners like aspartame, saccharin, or plant-based alternatives like stevia.
Beyond simply counting calories, we may need to think about how different sweeteners interact with our brain’s appetite regulation systems.
The USC research team is now conducting a follow-up study examining how calorie-free sweeteners affect the brains of children and adolescents, who consume more sugar and sugar substitutes than any other age group.
Points to Consider
Like any study, there are limitations and areas of concern when it comes to evaluating the findings. Here’s what readers should keep in mind:
Study Design Considerations
- This is a single-exposure study examining only acute responses to sucralose, not long-term consumption effects
- The crossover design is strong, but the artificial laboratory setting may not reflect real-world consumption patterns
- Participants consumed beverages in isolation, whereas sweeteners are typically consumed with other foods
Methodological Limitations
- The study focused solely on sucralose, not other popular artificial sweeteners (aspartame, stevia, etc.)
- Brain imaging techniques have spatial resolution limitations that make it difficult to identify effects in specific neuronal populations
- The study measured subjective hunger ratings but didn’t assess actual food intake following beverage consumption
Demographic Factors
- While the sample size (75 participants) is substantial for a brain imaging study, it may still limit statistical power for subgroup analyses
- The study included adults aged 18-35, so findings may not generalize to older populations
- Researchers noted different responses between males and females, warranting more sex-specific research
Funding and Support Context
- Research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIH grants R01DK102794, F31DK137584)
- While no conflicts of interest were declared, it’s worth noting that nutrition research can be influenced by competing scientific paradigms
Broader Context
- Randomized controlled trials on artificial sweeteners have shown neutral or beneficial effects on body weight, while observational studies have associated them with weight gain
- The complex mechanisms underlying appetite regulation involve multiple pathways beyond those examined in this study
More research is needed on how these acute brain responses translate to long-term eating behavior and weight outcomes. The findings don’t necessarily mean everyone should avoid artificial sweeteners, particularly those with conditions requiring sugar reduction. Results may have different implications for different individuals based on weight status and metabolic health.
Methodology Explained
This study employed a randomized crossover design where each participant tried all three test beverages (sucralose, sucrose, and water) on separate occasions. After fasting overnight for at least 12 hours, participants came to the laboratory where they consumed a 300ml beverage containing either sucralose (individually matched to taste as sweet as the sugar drink), sucrose (75g of regular sugar), or plain water. All drinks included a small amount of unsweetened cherry flavoring for palatability. Using a specialized brain imaging technique called pulsed arterial spin labeling (pASL), researchers measured blood flow in the hypothalamus before drinking and at 10 and 35 minutes afterward. This provided a measure of brain activity in specific regions related to appetite regulation. They simultaneously collected blood samples to measure glucose, insulin, and GLP-1 hormone levels, and participants rated their hunger on a scale from 1 to 10. For female participants, all testing occurred during the follicular phase of their menstrual cycle to minimize hormonal influences on hunger. This carefully controlled design allowed researchers to compare how the same person’s brain and body responded differently to each beverage.
Results Breakdown
The study revealed that consuming sucralose significantly increased blood flow in the hypothalamus compared to both sucrose and water, with the strongest effects observed in the lateral hypothalamus (often called the brain’s “hunger center”). Participants reported feeling much hungrier after drinking sucralose compared to sucrose, though hunger levels were similar between sucralose and water. Only the sugar-containing beverage raised blood glucose, insulin, and GLP-1 levels, and these increases corresponded with decreased hypothalamic activity—suggesting that metabolic signals directly influence brain appetite regulation. Connectivity analysis showed that sucralose altered functional connections between the hypothalamus and regions involved in motivation, reward processing, and sensory integration. These effects varied by weight status and insulin sensitivity, with healthy-weight individuals showing different patterns than those with overweight or obesity. Participants with lower insulin sensitivity (regardless of weight) showed stronger hypothalamic responses to sucralose, suggesting that metabolic health factors influence how the brain responds to non-caloric sweeteners.
Study Limitations
The researchers acknowledge several important constraints to their findings. First, they only examined immediate responses to a single dose of sucralose rather than long-term consumption patterns. The study focused specifically on sucralose, so the results might not apply to other non-caloric sweeteners with different chemical structures. Participants consumed the beverages in isolation, whereas in real life, sweeteners are typically consumed alongside other foods or within mixed meals, which could modify their effects. While the sample size of 75 participants was substantial for a brain imaging study, it still limited the statistical power for some subgroup analyses by weight status. The spatial resolution of the brain imaging techniques made it difficult to identify effects in specific neuronal populations within the hypothalamic subregions. Finally, although the study measured subjective hunger ratings, it didn’t assess actual food intake following beverage consumption, so it remains unclear whether these brain and physiological responses would meaningfully affect eating behavior.
Funding and Disclosures
This research was supported by grants from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102794 and F31DK137584). The researchers used a Research Electronic Data Capture (REDCap) database for data management, which was supported by the Southern California Clinical and Translational Science Institute through an NIH grant (UL1TR001855). All authors declared no competing interests that might have influenced the study design, execution, or interpretation of results.
Publication Information
This study titled “Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights” was published in Nature Metabolism (https://doi.org/10.1038/s42255-025-01227-8) in 2025. The research was conducted 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 from the University of Southern California and collaborating institutions. The paper represents findings from the “Brain Response to Sugar” study, which was registered on ClinicalTrials.gov (identifier: NCT02945475).
