The widely used sugar substitute sucralose may affect “key mechanisms” in the brain’s hypothalamus responsible for appetite regulation, a small randomized crossover trial suggested.
Compared with a sugar-sweetened drink, a noncaloric sucralose drink increased hypothalamic blood flow — a purported marker of hunger — as well as actual feelings of hunger. But compared with water alone, sucralose increased hypothalamic activity with no effect on hunger.
The findings suggest that the sweet taste alone may modulate hypothalamic activity, said principal investigator Kathleen Alanna Page, MD, director of the Diabetes and Obesity Research Institute at the Keck School of Medicine of the University of Southern California, Los Angeles.
Functional brain imaging also showed differences in communication between the hypothalamus and regions of the brain, including those involved in motivation and reward, an apparent effect of sucralose that varied by sex, body fat, and insulin resistance.
“We expected sucralose to affect the hypothalamus differently than sugar, but we were surprised by how strongly the hypothalamus of [study participants] with obesity responded to sucralose,” she told Medscape Medical News. “These differences in how brains and bodies respond to sucralose may help explain why previous studies have shown mixed results about its effects.”
The new study, published online in Nature Metabolism, is in line with Medscape Medical News’s previous report on potential harms from nonnutritive sweeteners. Sucralose was originally intended for individuals with obesity and diabetes but has become a common food ingredient.
Brain Response Differences
Researchers conducted a randomized crossover trial in a demographically diverse cohort that included 75 young adults aged 18-35 years. The mean age of these adults was 23 years; 57% were women. About one third of participants were Asian, 25% were Hispanic, 16% were non-Hispanic Black, and 28% were White. The aim was to test the acute effects of sucralose, sucrose, or a water control on changes in hypothalamic blood flow, circulating glucose levels, and hunger ratings.
Participants were separated into three groups: obese (n = 23), overweight (n = 24), and healthy weight (n = 28). They all came into the study with similar noncaloric sweetener use, researchers found.
On three separate visits, researchers collected baseline brain scans and blood samples, and participants rated how hungry they were. Participants then consumed 300 mL of water, a sugar-sweetened drink, or a drink sweetened with sucralose. Researchers collected follow-up brain scans, blood samples, and hunger ratings several times during the subsequent 2 hours.
Sucrose, but not sucralose, had a hunger-dampening effect while also raising peripheral glucose levels, which corresponded to reduced medial hypothalamic blood flow.
Acute consumption of sucralose vs sucrose stimulated hypothalamic blood flow and greater hunger responses.
Compared with water, sucralose also increased hypothalamic blood flow but did not produce a difference in participants’ hunger ratings.
Additional analyses showed that among individuals with healthy weight, sucralose produced greater activation of the hypothalamus than sucrose, whereas individuals with obesity showed a greater response in the lateral hypothalamic to sucralose relative to water.
Potential Effects on Cravings, Eating Behavior
In short-term tests, sucralose also led to evidence of increased signaling between the hypothalamus and the brain areas involved in motivation and decision-making, suggesting that the sweetener could affect cravings or eating behavior.
To look at functional connectivity — how brain regions communicate with each other — the team analyzed functional MRI scans. They found that sucralose, vs sucrose or water, resulted in increased functional connections between the hypothalamus and the brain regions involved in motivation and somatosensory processing, including the anterior cingulate cortex, which plays a role in decision-making. Researchers speculated that sucralose could affect food cravings and eating behavior.
The results also suggested that insulin resistance, independent of body mass index (BMI), is associated with heightened hypothalamic responses to sucralose compared with sucrose and water, the authors wrote. “Although exploratory, these findings point to a potential role of insulin resistance in modulating the hypothalamic response to noncaloric sweeteners.”
Further investigation revealed differences by sex. Female participants showed greater brain activity changes than male participants.
“Individual characteristics, such as sex, adiposity, and insulin resistance, appear to affect how the hypothalamus interprets sweet taste and metabolic signals related to appetite control,” the authors wrote. “This may be particularly relevant for noncaloric sweeteners like sucralose, which create a mismatch between the expectation of caloric intake and the absence of actual energy.”
This “mismatch” could lead to different hypothalamic activation patterns with sucralose vs caloric sweeteners, “which may ultimately influence appetite regulation and metabolic responses over time,” they concluded.
“It’s important to note this current study looks at the immediate effects of sucralose on appetite regulation in the brain,” Page said. “We need longer-term research to fully understand how noncaloric sweeteners influence cravings, food choices, and overall metabolic health over time.”
For now, she added, clinicians should advise patients to “aim to keep added sugars below 10% of total daily calories and not rely on noncaloric sweeteners as a regular substitute. Instead, try to reduce the overall intake of dietary sweeteners to support better metabolic health.”
Caution Urged
Susan Swithers, PhD, professor, Department of Psychological Sciences, and associate dean for Faculty Affairs at Purdue University, West Lafayette, Indiana, commented on the study for Medscape Medical News.
“These results add to our understanding of the ways in which high-intensity sweeteners like sucralose are not inert,” she said. “They produce effects in the brain that are different from those produced by sugars or by water, and ultimately, these differences could contribute to metabolic dysregulation.”
The results also suggest that specific subgroups of people might be more vulnerable to the effects of these sweeteners — for example, women whose BMI is in the obese range, noted Swithers, who was not involved in the study. “It will be important to follow-up on these findings to determine how consistent this is and to identify mechanisms which might convey this sensitivity.”
In general, the results reinforce the fact the brains of men and women show different responses to food-related stimuli. “This underscores how critical it is that science continues to include broad samples of people to identify mechanisms that could support such different responses,” she said.
Swithers pointed out that although the authors collected data from a relatively large number of people for a functional MRI study, “ultimately the total number of people within particular groups, when separated by sex and BMI status, was small. As a result, we want to be cautious about how much we can conclude based on these results alone.”
Nevertheless, she noted, the results are consistent with previous work indicating that noncaloric sweeteners produce brain-activity changes that are different from those caused by sugars. Therefore, “people should continue to be conscious of and cautious about the amounts of these sweeteners they consume, in the same way they attend to their intake of sugars.”
Page and Swithers declared having no competing interests. The study was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases.
Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.
