Artificial Sweetener Ups Appetite in Women, People With Obesity

Marlene Busko

October 05, 2021

A new study suggests that replacing sugar (sucrose) with the nonnutritive sweetener sucralose may not have the desired weight-loss effect, and in fact, it appears to increase appetite in women and people with obesity.

These are novel insights and further studies are needed, experts say.

After consuming a drink sweetened with sucralose versus sucrose, women and people with obesity had increased activity in the reward center of the brain and women ate more food at a post-fasting buffet.

"We were able to show that females and people with obesity may be more sensitive to artificial sweeteners," senior author Kathleen Page, MD, an associate professor of medicine at the Keck School of Medicine, University of Southern California, Los Angeles, summarized in a press release from the university.

"For these groups, drinking artificially sweetened drinks may trick the brain into feeling hungry, which may in turn result in more calories being consumed," she added.

Although many people use artificial sweeteners to try to lose weight, Page noted their place in a healthy diet is controversial. Some studies suggest they may be helpful, while others show they may contribute to weight gain, type 2 diabetes, and other metabolic disorders.

The new findings may partly explain these previous differences, she said.

The results also highlight the need to consider gender and body mass index in future research of nonnutritive sweeteners.

The study, by Alexandra G. Yunker, an MPH candidate in nutrition at Harvard University, Boston, Massachusetts, and colleagues, was published online September 28 in JAMA Network Open.

Novel Findings, Need to Consider Sex, Adiposity in Future Research

The current study "is of great importance as it provides novel insights into how adiposity and sex are associated with neural and behavioral outcomes of [nonnutritive sweetener] ingestion," Stephanie Kullmann, PhD, writes in an accompanying invited commentary.

"They show for the first time that female individuals with obesity are particularly vulnerable to greater neural responsivity elicited by acute sucralose consumption, particularly in prefrontal reward-associated brain regions," said Kullmann, a post-doctoral fellow at the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Zentrum München at the University of Tübingen in Germany.

This suggests "that adding nonnutritive sweeteners to our diet to increase sweetness could impair the brain's responsivity to food, with negative consequences for eating behavior and metabolism, particularly in women."

However, before being able to discourage use of nonnutritive sweeteners as part of a healthful diet, she cautioned, "we need further studies of their effects on a variety of neurobehavioral and metabolic outcomes."

The current study "clearly points out the importance of considering sex and adiposity in future research to [be able to] give individual tailored dietary recommendations for body weight management."

Invited to comment, John L. Sievenpiper, MD, PhD, associate professor in the Department of Nutritional Sciences and Medicine at the University of Toronto, Ontario, Canada, agreed that the data need to be reproduced.

Several questions remain, he stressed in an email to Medscape Medical News: "Was it the sucralose per se or the absence of calories that explains these findings? And the bigger question is, do these differences by adiposity and sex translate into weight gain?"

Systematic reviews and meta-analyses of the available randomized controlled trials of low and no calorie sweeteners including sucralose show the expected decrease in caloric intake and downstream weight loss in both males and females who are overweight or obese, he noted.

"It would be useful to understand if there are important interactions by adiposity and sex in future trials," Sievenpiper added.

Young Men and Women of Diverse Weight

Nonnutritive sweeteners are now used by more than 40% of US adults, the researchers write, but studies have reported mixed results on appetite, glucose metabolism, and body weight, and it is not clear whether these sweeteners are beneficial or harmful to health.

Prior research that was mainly in men and lean participants showed that brain areas involved in the regulation of taste, reward, and homeostasis may respond differently to nonnutritive versus nutritive sugars.

The researchers aimed to investigate this using initial data from the Brain Response to Sugar study (  

They analyzed data from 74 healthy 18- to 35-year-olds (58% women) with a mean age of 23. Overall, 37% had a healthy weight, 32% were overweight, and 31% had obesity.

Participants made three separate visits to the study center after a 12-hour overnight fast.

At each visit they drank 300 mL of water, a sucralose-sweetened drink, or a sucrose-sweetened drink.

They had blood drawn at baseline and at 10, 35, and 120 minutes after ingesting the drink.

At 20 minutes after consuming the drink, they had a functional MRI, during which they were shown 12 pictures of high-calorie, low-calorie, sweet, or savory foods and four pictures that were not foods and were asked to rank their appetite.

At 125 minutes after they ingested the drink, participants had access to a buffet meal.

"As expected, endocrine responses" — blood levels of glucose, insulin, and glucagon-like peptide-1 — "were greater after sucrose than sucralose ingestion," Kullmann noted, "but there were no significant differences based on sex and adiposity."  

However, "the most prominent and novel findings were observed on a neurobehavioral level," according to Kullmann.

That is, individuals with obesity (but not those with overweight or a healthy weight), had greater neural activity in the prefrontal reward-related areas of the brain, in response to savory food images, after ingesting a drink containing sucralose versus sucrose.

Similarly, after consuming a sucralose-sweetened drink as opposed to a sucrose-sweetened drink, female participants had greater activity in reward areas of the brain in response to food cues, especially high-calorie and sweet foods.

Women also consumed more calories at the buffet meal after they had ingested a sucralose-sweetened drink than after a sucrose-sweetened drink.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH). The Research Electronic Data Capture (REDCap) database used is supported by the Southern California Clinical and Translational Science Institute through an NIH grant. The researchers and editorialist have reported no relevant financial relationships.

JAMA Netw Open. 2021;4:e2126313, e2128047. Article, Editorial

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