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Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome

Nature volume 534, pages 213217 (09 June 2016) | Download Citation

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Abstract

Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient–gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.

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Change history

  • 28 June 2016

    The Reviewer Information section was included.

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European Nucleotide Archive

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Sequence data are deposited to the European Nucleotide Archive with accession code PRJEB13505.

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Acknowledgements

We thank J. Dong, Y. Nozaki, W. Zhu, X. Zhao, J. Stack, M. Kahn, B. Lim, and Y. Kosover for technical assistance. This study was funded by grants from the National Institutes of Health (R01 DK-40936, R01 AG-23686, P30 DK-45735, U24 DK-59635, T32 DK-101019, R01 DK-92606, R01 GM-103574 and DP2 GM-105456) and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Author information

Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Rachel J. Perry
    • , Liang Peng
    • , Gary W. Cline
    • , Rebecca L. Cardone
    • , Kitt Falk Petersen
    • , Richard G. Kibbey
    •  & Gerald I. Shulman
  2. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Natasha A. Barry
    •  & Andrew L. Goodman
  3. Microbial Sciences Institute, Yale University School of Medicine, New Haven, Connecticut 06516, USA

    • Natasha A. Barry
    •  & Andrew L. Goodman
  4. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, USA

    • Dongyan Zhang
    •  & Gerald I. Shulman
  5. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark

    • Kitt Falk Petersen
    •  & Gerald I. Shulman
  6. Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Richard G. Kibbey
    •  & Gerald I. Shulman

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Contributions

R.J.P., L.P., N.A.B., G.W.C., D.Z., and R.L.C. performed the in vivo and in vitro studies, and all authors analysed data. G.W.C., K.F.P., R.G.K., A.L.G., and G.I.S. provided critical advice for the experiments. Studies were designed and the manuscript was written by R.J.P. and G.I.S. with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gerald I. Shulman.

Reviewer Information Nature thanks D. Piomelli, C. Wollheim and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

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DOI

https://doi.org/10.1038/nature18309

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