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Gut microbiota
Original article
Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit
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  1. Zhuang Li1,2,
  2. Chun-Xia Yi3,
  3. Saeed Katiraei4,
  4. Sander Kooijman1,2,
  5. Enchen Zhou1,2,
  6. Chih Kit Chung1,
  7. Yuanqing Gao3,
  8. José K van den Heuvel1,2,
  9. Onno C Meijer1,2,
  10. Jimmy F P Berbée1,2,
  11. Marieke Heijink5,
  12. Martin Giera5,
  13. Ko Willems van Dijk2,4,
  14. Albert K Groen6,7,
  15. Patrick C N Rensen1,2,
  16. Yanan Wang1,2,7
  1. 1 Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
  3. 3 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  4. 4 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6 Department of Vascular Medicine, Amsterdam Diabetes Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  7. 7 Department of Pediatrics, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Yanan Wang, Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden 2300RC, The Netherlands; y.Wang{at}lumc.nl

Abstract

Objective Butyrate exerts metabolic benefits in mice and humans, the underlying mechanisms being still unclear. We aimed to investigate the effect of butyrate on appetite and energy expenditure, and to what extent these two components contribute to the beneficial metabolic effects of butyrate.

Design Acute effects of butyrate on appetite and its method of action were investigated in mice following an intragastric gavage or intravenous injection of butyrate. To study the contribution of satiety to the metabolic benefits of butyrate, mice were fed a high-fat diet with butyrate, and an additional pair-fed group was included. Mechanistic involvement of the gut-brain neural circuit was investigated in vagotomised mice.

Results Acute oral, but not intravenous, butyrate administration decreased food intake, suppressed the activity of orexigenic neurons that express neuropeptide Y in the hypothalamus, and decreased neuronal activity within the nucleus tractus solitarius and dorsal vagal complex in the brainstem. Chronic butyrate supplementation prevented diet-induced obesity, hyperinsulinaemia, hypertriglyceridaemia and hepatic steatosis, largely attributed to a reduction in food intake. Butyrate also modestly promoted fat oxidation and activated brown adipose tissue (BAT), evident from increased utilisation of plasma triglyceride-derived fatty acids. This effect was not due to the reduced food intake, but explained by an increased sympathetic outflow to BAT. Subdiaphragmatic vagotomy abolished the effects of butyrate on food intake as well as the stimulation of metabolic activity in BAT.

Conclusion Butyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.

  • short-chain fatty acids
  • obesity
  • appetite
  • energy metabolism
  • brain/gut interaction

https://doi.org/10.1136/gutjnl-2017-314050

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    Footnotes

    • Contributors ZL: study concept and design; acquisition of data; analysis and interpretation of data; edited and revised the manuscript. CY, SK, SK, EZ, CKC, YG, JKH, MH: acquisition of data; analysis and interpretation of data; edited and revised the manuscript. OCM, MG, JFPB, KW: edited and revised the manuscript. AKG, PCNR: study concept and design; obtained funding; study supervision; edited and revised the manuscript. YW: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; obtained funding.

    • Funding This study was supported by the EU grant FP7-HEALTH-305707 (AKG): ‘A systems biology approach to RESOLVE the molecular pathology of two hallmarks of patients with metabolic syndrome and its co-morbidities; hypertriglyceridemia and low HDL-cholesterol’, and ‘the Netherlands Cardio Vascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences’ for the GENIUS project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2011-9). CXY is supported by an AMC fellowship (2014) and the Dutch Diabetes Fonds (2015.82.1826). YW is supported by a VENI grant from NWO-ZonMW (91617027). PCNR is an Established Investigator of the Netherlands Heart Foundation (grant 2009T038).

    • Competing interests None declared.

    • Ethics approval The Institutional Ethics Committee for Animal Care and Experiments from the Leiden University Medical Center, Leiden, The Netherlands, approved the protocol.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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