The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage

Romain Girard, Sarah Tremblay, Christophe Noll, Stéphanie St-Jean, Christine Jones, Yves Gélinas, Faïza Maloum-Rami, Nathalie Perreault, Mathieu Laplante, André C. Carpentier and François Boudreau ()
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Romain Girard: Université de Sherbrooke
Sarah Tremblay: Université de Sherbrooke
Christophe Noll: Université de Sherbrooke
Stéphanie St-Jean: Université de Sherbrooke
Christine Jones: Université de Sherbrooke
Yves Gélinas: Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Faculty of Medicine, Université Laval
Faïza Maloum-Rami: Université de Sherbrooke
Nathalie Perreault: Université de Sherbrooke
Mathieu Laplante: Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Faculty of Medicine, Université Laval
André C. Carpentier: Université de Sherbrooke
François Boudreau: Université de Sherbrooke

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

Date: 2022
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DOI: 10.1038/s41467-021-27934-w

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