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Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production

Nature volume 452, pages 1012–1016 (2008)Cite this article

Abstract

Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine–brain axis1,2,3,4. In parallel, a brain–liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents5. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine–brain–liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine–brain–liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.

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Figure 1: Upper intestinal lipids suppress liver glucose production.
Figure 2: Upper intestinal lipids suppress glucose production through a neuronal network.
Figure 3: Upper intestinal lipids suppress glucose production by activating an intestine–NTS–liver neurocircuitry.

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Acknowledgements

We thank C. Baveghems for technical assistance. This work is supported by a research grant to T.K.T.L. from the Canadian Institute of Health Research (MOP-82701). R.G.-J. is supported by the National Institutes of Health (DK45024). G.J.S. is supported by the National Institutes of Health (DK47208) and the Skirball Institute. T.K.T.L. holds the John Kitson McIvor Endowed Chair in Diabetes Research at the University Health Network and the University of Toronto.

Author Contributions P.Y.T.W. conducted and designed experiments, performed data analyses and wrote the manuscript; L.C., C.K.L.L., M.C. and M.A. conducted experiments; X.L. assisted in surgical procedures; P.E.L. and R.G.-J. assisted in LCFA-CoA measurements; G.J.S. assisted in surgical procedures and designed experiments; and T.K.T.L. supervised the project, designed experiments and wrote the manuscript.

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Authors and Affiliations

  1. Toronto General Hospital Research Institute, University Health Network, Toronto M5G 1L7, Canada

    Penny Y. T. Wang, Liora Caspi, Carol K. L. Lam, Madhu Chari, Michelle Ang & Tony K. T. Lam

  2. Department of Physiology, and,

    Carol K. L. Lam, Madhu Chari & Tony K. T. Lam

  3. Department of Medicine, University of Toronto, Toronto M5S 1A8, Canada,

    Tony K. T. Lam

  4. Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA,

    Xiaosong Li, Roger Gutierrez-Juarez & Gary J. Schwartz

  5. Department of Pharmacology, University of Alberta, Edmonton T6G 2H7, Canada

    Peter E. Light

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Correspondence to Tony K. T. Lam.

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The file contains Supplementary Methods, Supplementary Tables S1-S2 and Supplementary Figures S1-S2 with Legends (PDF 286 kb)

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Wang, P., Caspi, L., Lam, C. et al. Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production. Nature 452, 1012–1016 (2008). https://doi.org/10.1038/nature06852

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