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Intestinal gluconeogenesis: metabolic benefits make sense in the light of evolution

Nature Reviews Gastroenterology & Hepatology volume 20, pages 183–194 (2023)Cite this article

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Abstract

The intestine, like the liver and kidney, in various vertebrates and humans is able to carry out gluconeogenesis and release glucose into the blood. In the fed post-absorptive state, intestinal glucose is sensed by the gastrointestinal nervous system. The latter initiates a signal to the brain regions controlling energy homeostasis and stress-related behaviour. Intestinal gluconeogenesis (IGN) is activated by several complementary mechanisms, in particular nutritional situations (for example, when food is enriched in protein or fermentable fibre and after gastric bypass surgery in obesity). In these situations, IGN has several metabolic and behavioural benefits. As IGN is activated by nutrients capable of fuelling systemic gluconeogenesis, IGN could be a signal to the brain that food previously ingested is suitable for maintaining plasma glucose for a while. This process might account for the benefits observed. Finally, in this Perspective, we discuss how the benefits of IGN in fasting and fed states could explain why IGN emerged and was maintained in vertebrates by natural selection.

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Fig. 1: Sequence from nutrient induction of IGN to glucose detection in the portal vein.
Fig. 2: Metabolic processes targeted by IGN.
Fig. 3: Brain targets of IGN.
Fig. 4: Evolution of G6PC genes.
Fig. 5: Changes in EGP during human evolution concerning food habits.
Fig. 6: Proposed sequence of signals to the brain concerning the presence and absence of food and its composition.

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Data availability

Accession numbers of the amino acid sequences used for Fig. 4 are provided as an Excel spreadsheet (Supplementary Table 1); each row corresponds to a protein-coding gene. Protein-coding genes present in the phylogenetic tree of Fig. 4b are indicated in red. The sequence alignment corresponding to the TreeFam family TF324388 is provided as a text file (Supplementary Table 2). These data were freely obtained from the TreeFam v9 database hosted at the European Bioinformatics Institute (EBI).

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Acknowledgements

The authors thank their team and the countless number of past members and collaborators, without whom the work analysed herein would not have been possible, and more particularly F. Rajas, J. Vily-Petit and E. Van Obberghen for critical reading and help in the preparation of the manuscript, and G. Escarguel, V. Balter and Y. Voituron for help in relation to the evolution of human nutrition. The authors are also grateful to the University Claude Bernard Lyon 1 and INSERM for hosting and funding their laboratory and the INRAe and the CNRS for funding their salary.

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  1. Institut National de la Santé et de la Recherche Médicale U1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France

    Amandine Gautier-Stein & Gilles Mithieux

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Gautier-Stein, A., Mithieux, G. Intestinal gluconeogenesis: metabolic benefits make sense in the light of evolution. Nat Rev Gastroenterol Hepatol 20, 183–194 (2023). https://doi.org/10.1038/s41575-022-00707-6

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