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


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.


  1. Badman, M. K. & Flier, J. S. The gut and energy balance: visceral allies in the obesity wars. Science 307, 1909–1914 (2005)

    Article  ADS  CAS  Google Scholar 

  2. Cummings, D. E. & Overduin, J. Gastrointestinal regulation of food intake. J. Clin. Invest. 117, 13–23 (2007)

    Article  CAS  Google Scholar 

  3. Moran, T. H. & Schwartz, G. J. Neurobiology of cholecystokinin. Crit. Rev. Neurobiol. 9, 1–28 (1994)

    CAS  PubMed  Google Scholar 

  4. Murphy, K. G. & Bloom, S. R. Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859 (2006)

    Article  ADS  CAS  Google Scholar 

  5. Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nature Med. 11, 320–327 (2005)

    Article  CAS  Google Scholar 

  6. Greenberg, D., Smith, G. P. & Gibbs, J. Intraduodenal infusions of fats elicit satiety in sham-feeding rats. Am. J. Physiol. 259, R110–R118 (1990)

    Article  CAS  Google Scholar 

  7. Matzinger, D. et al. The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans. Gut 46, 689–693 (2000)

    Article  Google Scholar 

  8. Monnikes, H. et al. Pathways of Fos expression in locus ceruleus, dorsal vagal complex, and PVN in response to intestinal lipid. Am. J. Physiol. 273, R2059–R2071 (1997)

    CAS  PubMed  Google Scholar 

  9. Sclafani, A., Ackroff, K. & Schwartz, G. J. Selective effects of vagal deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal nutrients. Physiol. Behav. 78, 285–294 (2003)

    Article  CAS  Google Scholar 

  10. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004)

    Article  ADS  CAS  Google Scholar 

  11. Lam, T. K., Schwartz, G. J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nature Neurosci. 8, 579–584 (2005)

    Article  CAS  Google Scholar 

  12. Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000)

    Article  CAS  Google Scholar 

  14. Coll, A. P., Farooqi, I. S. & O’Rahilly, S. The hormonal control of food intake. Cell 129, 251–262 (2007)

    Article  CAS  Google Scholar 

  15. Coppari, R. et al. The hypothalamic arcuate nucleus: A key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab. 1, 63–72 (2005)

    Article  CAS  Google Scholar 

  16. Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nature Med. 12, 917–924 (2006)

    Article  CAS  Google Scholar 

  17. Lam, T. K., Gutierrez-Juarez, R., Pocai, A. & Rossetti, L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947 (2005)

    Article  ADS  CAS  Google Scholar 

  18. Schwartz, M. W. & Porte, D. Diabetes, obesity, and the brain. Science 307, 375–379 (2005)

    Article  ADS  CAS  Google Scholar 

  19. Lam, T. K. et al. Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nature Med. 13, 171–180 (2007)

    Article  CAS  Google Scholar 

  20. Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Med. 9, 756–761 (2003)

    Article  CAS  Google Scholar 

  21. Greenberg, D., Kava, R. A., Lewis, D. R., Greenwood, M. R. & Smith, G. P. Time course for entry of intestinally infused lipids into blood of rats. Am. J. Physiol. 269, R432–R436 (1995)

    CAS  PubMed  Google Scholar 

  22. Aicher, S. A., Sharma, S. & Pickel, V. M. N-methyl-d-aspartate receptors are present in vagal afferents and their dendritic targets in the nucleus tractus solitarius. Neuroscience 91, 119–132 (1999)

    Article  CAS  Google Scholar 

  23. Berthoud, H. R., Earle, T., Zheng, H., Patterson, L. M. & Phifer, C. Food-related gastrointestinal signals activate caudal brainstem neurons expressing both NMDA and AMPA receptors. Brain Res. 915, 143–154 (2001)

    Article  CAS  Google Scholar 

  24. Covasa, M., Hung, C. Y., Ritter, R. C. & Burns, G. A. Intracerebroventricular administration of MK-801 increases food intake through mechanisms independent of gastric emptying. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1462–R1467 (2004)

    Article  CAS  Google Scholar 

  25. Treece, B. R., Covasa, M., Ritter, R. C. & Burns, G. A. Delay in meal termination follows blockade of N-methyl-d-aspartate receptors in the dorsal hindbrain. Brain Res. 810, 34–40 (1998)

    Article  CAS  Google Scholar 

  26. Pocai, A. et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006)

    Article  CAS  Google Scholar 

  27. Caspi, L., Wang, P. Y. & Lam, T. K. A balance of lipid-sensing mechanisms in the brain and liver. Cell Metab. 6, 99–104 (2007)

    Article  CAS  Google Scholar 

  28. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)

    Article  ADS  CAS  Google Scholar 

  29. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)

    Article  ADS  Google Scholar 

  30. Cummings, D. E., Overduin, J. & Foster-Schubert, K. E. Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J. Clin. Endocrinol. Metab. 89, 2608–2615 (2004)

    Article  CAS  Google Scholar 

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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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Correspondence to Tony K. T. Lam.

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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).

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