Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF-4γ: A Critical Role for Enteroendocrine Cell Lineage

Diabetes. 2015 Aug;64(8):2744-56. doi: 10.2337/db14-0993. Epub 2015 Mar 31.


Intestine contributes to energy homeostasis through the absorption, metabolism, and transfer of nutrients to the organism. We demonstrated previously that hepatocyte nuclear receptor-4α (HNF-4α) controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4γ, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4γ knockout mice, we detect an exaggerated insulin peak and improvement in glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2, and Hnf4a, leading to an increase of both GLP-1-positive cell number and basal and stimulated GLP-1 plasma levels potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin (9-39), we demonstrate a direct effect of GLP-1 on improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic β-cells, and we report an increase of the β-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4γ improves glucose homeostasis through a modulation of the enteroendocrine cell lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Cell Lineage / physiology*
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / metabolism*
  • Glucose Tolerance Test
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Homeostasis / physiology
  • Insulin / blood*
  • Intestinal Mucosa / metabolism*
  • Mice
  • Mice, Knockout


  • Blood Glucose
  • Hepatocyte Nuclear Factor 4
  • Hnf4g protein, mouse
  • Insulin