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

Nature Metabolism volume 7, pages 574–585 (2025)Cite this article

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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.

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Fig. 1: Participant enrollment flowchart for the Randomized Crossover Brain Response to Sugar II trial and final analysis.
Fig. 2: Schematic of study design.
Fig. 3: Differential hypothalamic response to drink comparisons.
Fig. 4: Difference in hypothalamic response to drinks by weight status.
Fig. 5: Differential functional connectivity from hypothalamus seed region after sucralose ingestion relative to sucrose and water.
Fig. 6: Visual display of changes in hypothalamic, peripheral glucose, insulin, GLP-1 and hunger responses over time.
Fig. 7: Associations between peripheral glucose, hunger and changes in medial hypothalamic blood flow.

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Data availability

The datasets generated and analysed during the current study are available from the corresponding author (K.A.P.) on reasonable request, and all brain imaging data are available in the Open Science Framework repository (https://osf.io/tuw93). Access to individual-level data is restricted owing to ethical and legal concerns. However, data may be shared for scientific collaborations upon request, contingent on the execution of appropriate data-sharing agreements. All requests will undergo review and approval by investigators, and will be in compliance with relevant local and national regulations and data-sharing policies. To request access, please contact the corresponding author. An initial response to requests will be provided within four weeks. Source data are provided with this paper.

Code availability

Computer codes used for data analyses are published in the following Open Science Framework repository: https://osf.io/tuw93/.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102794 to K.A.P, F31DK137584 to S.P.C). A Research Electronic Data Capture, REDCap, database was used for this study, which is supported by the Southern California Clinical and Translational Science Institute through NIH grant UL1TR001855. We thank the volunteers who participated in this study and the staff at the Dornsife Cognitive Neuroimaging Center and Diabetes and Obesity Research Institute of the University of Southern California. A. Romero, E. Trigo, R. Maniego, H. Dorton, E. Jahng, B. Ge, L. N. Overholtzer, J. Hislop, M. Erdstein and P. Dave (all from University of Southern California) assisted with study visits and recruiting volunteers.

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  1. These authors jointly supervised this work: Stephanie Kullmann, Kathleen A. Page.

Authors and Affiliations

  1. Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA

    Sandhya P. Chakravartti, John R. Monterosso & Kathleen A. Page

  2. Division of Endocrinology and Diabetes, Department of Medicine & Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Sandhya P. Chakravartti, Hanyang Liu, Alexandra G. Yunker, Brendan Angelo & Kathleen A. Page

  3. Diabetes and Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Sandhya P. Chakravartti, Hanyang Liu, Alexandra G. Yunker, Brendan Angelo & Kathleen A. Page

  4. Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Kay Jann

  5. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany

    Ralf Veit & Stephanie Kullmann

  6. Department of Psychology, University Southern California, Los Angeles, CA, USA

    John R. Monterosso

  7. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA

    Anny H. Xiang

  8. Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, Eberhard Karls University Tübingen, Tübingen, Germany

    Stephanie Kullmann

  9. German Center for Diabetes Research (DZD), Tübingen, Germany

    Stephanie Kullmann

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Contributions

K.A.P. conceived and designed the study. All authors were involved with the acquisition, analysis or interpretation of data. S.P.C. and K.A.P. drafted the manuscript; S.P.C., K.A.P., S.K., R.V., K.J., J.R.M., A.H.X. and A.G.Y. critically reviewed the manuscript for important intellectual content. S.P.C. performed statistical analysis. S.P.C., H.L. and B.A. visualized the project. H.L., A.G.Y., B.A., K.J. and R.V. provided administrative, technical or material support. K.A.P. obtained funding and supervised the research.

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Correspondence to Kathleen A. Page.

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Extended data

Extended Data Fig. 1 Visual Display of Hypothalamic ROI.

Hypothalamic Region of interest (ROIs) and corresponding coordinates. (a) Lateral hypothalamus (green), (b) Medial hypothalamus (blue), (c) Neudorfer (yellow). The images are displayed in neurological convention.

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Supplementary Tables 1–10; Supplementary File 1, Study Protocol, Statistical Analysis Plan

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Source Data Fig. 7

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Chakravartti, S.P., Jann, K., Veit, R. et al. Non-caloric sweetener effects on brain appetite regulation in individuals across varying body weights. Nat Metab 7, 574–585 (2025). https://doi.org/10.1038/s42255-025-01227-8

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