Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights

Abstract

Sucralose, a widely used non-caloric sweetener, provides sweet taste without calories. Some studies suggest that non-caloric sweeteners stimulate appetite, possibly owing to the delivery of a sweet taste without the post-ingestive metabolic signals that normally communicate with the hypothalamus to suppress hunger. In a randomized crossover trial (ClinicalTrials.gov identifier: NCT02945475), 75 young adults (healthy weight, overweight or with obesity) consumed a drink containing sucralose, sweetness-matched sucrose or water. We show that acute consumption of sucralose versus sucrose stimulates hypothalamic blood flow (P < 0.018) and greater hunger responses (P < 0.001). Sucralose versus water also increases hypothalamic blood flow (P < 0.019) but produces no difference in hunger ratings. Sucrose, but not sucralose, increases peripheral glucose levels, which are associated with reductions in medial hypothalamic blood flow (P < 0.007). Sucralose, compared to sucrose and water, results in increased functional connections between the hypothalamus and brain regions involved in motivation and somatosensory processing. These findings suggest that non-caloric sweeteners could affect key mechanisms in the hypothalamus responsible for appetite regulation.

Full text

Nature Metabolism | Volume 7 | March 2025 | 574–585 574
nature metabolism
Article
https://doi.org/10.1038/s42255-025-01227-8
Non-caloric sweetener effects on brain
appetite regulation in individuals across
varying body weights
Sandhya P. Chakravartti 1,2,3, Kay Jann 4, Ralf Veit 5, Hanyang Liu2,3,
Alexandra G. Yunker2,3, Brendan Angelo 2,3, John R. Monterosso1,6,
Anny H. Xiang7, Stephanie Kullmann 5,8,9,10 & Kathleen A. Page 1,2,3,10
Sucralose, a widely used non-caloric sweetener, provides sweet taste without
calories. Some studies suggest that non-caloric sweeteners stimulate appetite,
possibly owing to the delivery of a sweet taste without the post-ingestive
metabolic signals that normally communicate with the hypothalamus to
suppress hunger. In a randomized crossover trial (ClinicalTrials.gov identier:
NCT02945475), 75 young adults (healthy weight, overweight or with obesity)
consumed a drink containing sucralose, sweetness-matched sucrose or water.
We show that acute consumption of sucralose versus sucrose stimulates
hypothalamic blood ow (P < 0.018) and greater hunger responses (P < 0.001).
Sucralose versus water also increases hypothalamic blood ow (P < 0.019)
but produces no dierence in hunger ratings. Sucrose, but not sucralose,
increases peripheral glucose levels, which are associated with reductions
in medial hypothalamic blood ow (P < 0.007). Sucralose, compared to
sucrose and water, results in increased functional connections between the
hypothalamus and brain regions involved in motivation and somatosensory
processing. These ndings suggest that non-caloric sweeteners could aect
key mechanisms in the hypothalamus responsible for appetite regulation.
Obesity rates have risen dramatically over the last three decades, posing
a significant public health challenge
1
. A growing body of evidence links
the rise in sugar-sweetened beverage consumption to weight gain and
obesity2–4. To address this issue, non-caloric sweeteners are increasingly
being consumed as a calorie-free alternative to satisfy the craving for
sweetness2. Although non-caloric sweeteners are widely used, recent
reviews have raised concerns about their potential adverse effects on
cardiometabolic health3,5–10, and their effects on body weight remain
inconclusive. Although prospective cohort studies have associated
non-caloric sweetener consumption with weight gain4 and obesity5, ran-
domized controlled trials have reported neutral or beneficial effects on
body weight
7,11–15
. Studies conducted in rodents suggest that non-caloric
sweeteners stimulate hunger by interfering with the conventional neu-
ral responses to sweet taste and nutrient signalling that occur with
caloric sugar16. Human studies using functional magnetic resonance
imaging (fMRI) also indicate that the brain may respond differently
Received: 4 July 2024
Accepted: 31 January 2025
Published online: 26 March 2025
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1Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA. 2Division of Endocrinology and Diabetes, Department of
Medicine & Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 3Diabetes and Obesity Research Institute,
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 4Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck
School of Medicine, University of Southern California, Los Angeles, CA, USA. 5Institute for Diabetes Research and Metabolic Diseases of the Helmholtz
Center Munich at the University of Tübingen, Tübingen, Germany. 6Department of Psychology, University Southern California, Los Angeles, CA, USA.
7Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA. 8Department of Internal Medicine, Division of
Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany. 9German Center for Diabetes Research (DZD),
Tübingen, Germany. 10These authors jointly supervised this work: Stephanie Kullmann, Kathleen A. Page. e-mail: kpage@usc.edu
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