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

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.

HNF4α Acts as Upstream Functional Regulator of Intestinal Wnt3 and Paneth Cell Fate

“…These functions were altered in Hnf4a Δ IEC mice exposed to radiation, 30 inflammatory stress, 29 , 48 or a high-fat diet. 49 Collectively, these observations indicate that the study of HNF4α function in enteroids could be an asset in dissecting the contribution of the epithelial versus mesenchymal niche contribution to intestinal homeostasis, particularly in conditions that mimic pathologic situations.…”

Molecular mechanisms of action of metformin: latest advances and therapeutic implications

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