Abstract
Mutations in the HNF4A gene cause MODY1 and are associated with an increased risk of Type 2 diabetes mellitus. On the other hand, incretins are hormones that potentiate reductions in blood glucose levels. Given the established role of incretin-based therapy to treat diabetes and metabolic disorders, we investigated a possible regulatory link between intestinal epithelial HNF4α and glucose-dependent insulinotropic polypeptide (GIP), an incretin that is specifically produced by gut enteroendocrine cells. Conditional deletion of HNF4α in the whole intestinal epithelium was achieved by crossing Villin-Cre and Hnf4αloxP/loxP C57BL/6 mouse models. GIP expression was measured by qPCR, immunofluorescence and ELISA. Gene transcription was assessed by luciferase and electrophoretic mobility shift assays. Metabolic parameters were analyzed by indirect calorimetry and dual-energy X-ray absorptiometry. HNF4α specific deletion in the intestine led to a reduction in GIP. HNF4α was able to positively control Gip transcriptional activity in collaboration with GATA-4 transcription factor. Glucose homeostasis and glucose-stimulated insulin secretion remained unchanged in HNF4α deficient mice. Changes in GIP production in these mice did not impact nutrition or energy metabolism under normal physiology but led to a reduction of bone area and mineral content, a well described physiological consequence of GIP deficiency. Our findings point to a novel regulatory role between intestinal HNF4α and GIP with possible functional impact on bone density.
Highlights
Hepatocyte nuclear factor - 4 alpha (HNF4α) is a transcription factor that belongs to the steroid/thyroid hormone receptor superfamily originally identified as a liver-enriched transcription factor and expressed in gastrointestinal epithelia, the pancreas and kidneys[1,2,3]
Incretins that comprise intestinal specific glucose-dependent insulinotropic polypeptide (GIP) actively contribute to glucose-stimulated insulin secretion (GSIS) by enhancing insulin secretion upon glucose sensing by pancreatic β-cells, and are involved in a number of other biological activities including bone metabolism[21]
The present study aimed to investigate whether intestinal epithelial HNF4α influences GIP regulation, glucose homeostasis and metabolism in mice
Summary
Hepatocyte nuclear factor - 4 alpha (HNF4α) is a transcription factor that belongs to the steroid/thyroid hormone receptor superfamily originally identified as a liver-enriched transcription factor and expressed in gastrointestinal epithelia, the pancreas and kidneys[1,2,3]. The targeted loss of Hnf4α in pancreatic β-cells was not sufficient to cause hypoinsulinemia and there are conflicting reports as to whether HNF4α is crucial in sustaining GSIS in these murine models[11,12] These observations suggest that other HNF4α-defective tissues could be involved to fully recapitulate MODY1 pathogenesis[11,12]. Enteroendocrine cells from the intestinal epithelium produce a wide range of peptides mediating digestive rate, bone remodeling, appetite, GSIS, adipogenesis and global energy homeostasis control Among these various peptides, incretins that comprise intestinal specific glucose-dependent insulinotropic polypeptide (GIP) actively contribute to GSIS by enhancing insulin secretion upon glucose sensing by pancreatic β-cells, and are involved in a number of other biological activities including bone metabolism[21]. We report that conditional deletion of Hnf4a in the intestinal murine epithelium significantly reduces GIP production, impacts bone density but does not influence whole body energy metabolism under normal physiological conditions
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