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

Penny Y T Wang, Liora Caspi, Carol K L Lam, Madhu Chari, Xiaosong Li, Peter E. Light, Roger Gutierrez-Juarez, Michelle Ang, Gary J. Schwartz, Tony K T Lam

Research output: Contribution to journalArticle

202 Citations (Scopus)

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 axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. 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.

Original languageEnglish (US)
Pages (from-to)1012-1016
Number of pages5
JournalNature
Volume452
Issue number7190
DOIs
StatePublished - Apr 24 2008

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Lipids
Glucose
Liver
Brain
Intestines
Acyl Coenzyme A
Homeostasis
Vagotomy
Rodentia
Eating
Tetracaine
Fourth Ventricle
Solitary Nucleus
Dizocilpine Maleate
Ion Channels
Aspartic Acid
Anesthetics
Digestion
Food

ASJC Scopus subject areas

  • General

Cite this

Wang, P. Y. T., Caspi, L., Lam, C. K. L., Chari, M., Li, X., Light, P. E., ... Lam, T. K. T. (2008). Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature, 452(7190), 1012-1016. https://doi.org/10.1038/nature06852

Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. / Wang, Penny Y T; Caspi, Liora; Lam, Carol K L; Chari, Madhu; Li, Xiaosong; Light, Peter E.; Gutierrez-Juarez, Roger; Ang, Michelle; Schwartz, Gary J.; Lam, Tony K T.

In: Nature, Vol. 452, No. 7190, 24.04.2008, p. 1012-1016.

Research output: Contribution to journalArticle

Wang, PYT, Caspi, L, Lam, CKL, Chari, M, Li, X, Light, PE, Gutierrez-Juarez, R, Ang, M, Schwartz, GJ & Lam, TKT 2008, 'Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production', Nature, vol. 452, no. 7190, pp. 1012-1016. https://doi.org/10.1038/nature06852
Wang PYT, Caspi L, Lam CKL, Chari M, Li X, Light PE et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 2008 Apr 24;452(7190):1012-1016. https://doi.org/10.1038/nature06852
Wang, Penny Y T ; Caspi, Liora ; Lam, Carol K L ; Chari, Madhu ; Li, Xiaosong ; Light, Peter E. ; Gutierrez-Juarez, Roger ; Ang, Michelle ; Schwartz, Gary J. ; Lam, Tony K T. / Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. In: Nature. 2008 ; Vol. 452, No. 7190. pp. 1012-1016.
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