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Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study

Nature Metabolism volume 5, pages 1059–1072 (2023)Cite this article

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Abstract

Post-ingestive nutrient signals to the brain regulate eating behaviour in rodents, and impaired responses to these signals have been associated with pathological feeding behaviour and obesity. To study this in humans, we performed a single-blinded, randomized, controlled, crossover study in 30 humans with a healthy body weight (females N = 12, males N = 18) and 30 humans with obesity (females N = 18, males N = 12). We assessed the effect of intragastric glucose, lipid and water (noncaloric isovolumetric control) infusions on the primary endpoints cerebral neuronal activity and striatal dopamine release, as well as on the secondary endpoints plasma hormones and glucose, hunger scores and caloric intake. To study whether impaired responses in participants with obesity would be partially reversible with diet-induced weight loss, imaging was repeated after 10% diet-induced weight loss. We show that intragastric glucose and lipid infusions induce orosensory-independent and preference-independent, nutrient-specific cerebral neuronal activity and striatal dopamine release in lean participants. In contrast, participants with obesity have severely impaired brain responses to post-ingestive nutrients. Importantly, the impaired neuronal responses are not restored after diet-induced weight loss. Impaired neuronal responses to nutritional signals may contribute to overeating and obesity, and ongoing resistance to post-ingestive nutrient signals after significant weight loss may in part explain the high rate of weight regain after successful weight loss.

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Fig. 1: Schematics of the study design and main study procedures.
Fig. 2: Participant flow diagram.
Fig. 3: Effect of intragastric glucose and lipid infusions on glucose, insulin and gut hormones.
Fig. 4: BOLD signal following intragastric glucose and lipid infusions (controlled for intragastric water infusions) in lean participants and participants with obesity before and after weight loss.
Fig. 5: Dopamine release following intragastric glucose and lipid infusions in lean participants and participants with obesity before and after weight loss.
Fig. 6: Strong GLP-1 release following intragastric lipids is associated with more pronounced changes in the striatal BOLD signal, only in lean participants.

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Data availability

Free access to individual data is restricted due to ethical/legal concerns. However, upon request, the data may be made available for scientific collaborations after the execution of appropriate data sharing agreements, after review and approval of requests by the medical ethics committee, participants and investigators in line with existing local/national regulations and data sharing agreements. Requests can be sent to the corresponding author. A first response to requests will follow within 4 weeks. Source data are provided with this paper.

Code availability

Computer codes used for data analyses will be published in a repository on GitHub: https://github.com/MJMSerlie/SPIN-Study.

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Acknowledgements

We acknowledge the volunteers who participated in our study, and the magnetic resonance and SPECT technicians and students for their assistance during the study. We also thank J. Hillebrand from the Laboratory of Endocrinology for assistance with the GLP-1 and ghrelin assays. J.B. is supported by NWO ZonMw medium-sized investments grant 16366. G.J.S. is supported by the National Institutes of Health grant P30DK026687. M.J.S. received an unrestricted research grant from Mediq-TEFA bv.

Author information

Authors and Affiliations

  1. Amsterdam UMC, location AMC, Department of Radiology and Nuclear Medicine, Amsterdam, the Netherlands

    Katy A. van Galen, Anouk Schrantee & Jan Booij

  2. Amsterdam University Medical Centers (UMC), location AMC, Department of Endocrinology and Metabolism and Amsterdam Gastroenterology Metabolism Endocrinology Institute, Amsterdam, the Netherlands

    Kasper W. ter Horst, Susanne E. la Fleur & Mireille J. Serlie

  3. Amsterdam UMC, location AMC, Department of Clinical Chemistry, Laboratory of Endocrinology, Amsterdam, the Netherlands

    Susanne E. la Fleur

  4. Yale University School of Medicine, Department of Radiology and Biomedical Imaging, New Haven, CT, USA

    R. Todd Constable

  5. Albert Einstein College of Medicine, Fleischer Institute for Diabetes and Metabolism, Bronx, NY, USA

    Gary J. Schwartz

  6. Yale University School of Medicine, Department of Psychiatry, New Haven, CT, USA

    Ralph J. DiLeone

  7. Yale University School of Medicine, Department of Endocrinology, New Haven, CT, USA

    Mireille J. Serlie

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Contributions

Conceptualization, K.A.G., K.W.H., S.E.F., J.B. and M.J.S.; methodology, K.A.G., A.S., K.W.H., S.E.F., J.B. and M.J.S.; software, K.A.G. and A.S.; investigation and formal analysis, K.A.G. and A.S.; writing—original draft, K.A.G.; writing—review and editing, A.S., K.W.H., S.E.F., J.B., R.T.C., G.J.S., R.J.D. and M.J.S.; visualization, K.A.G., A.S. and K.W.H.; supervision, K.W.H. and M.J.S.; project administration, K.A.G.; funding acquisition, M.J.S.

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Correspondence to Mireille J. Serlie.

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Nature Metabolism thanks Alexandra DiFeliceantonio, Kathleen Page and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Missing data, fMRI preprocessing, Supplementary Tables 1–4 and study protocol.

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van Galen, K.A., Schrantee, A., ter Horst, K.W. et al. Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study. Nat Metab 5, 1059–1072 (2023). https://doi.org/10.1038/s42255-023-00816-9

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