Intestinal Epithelial NAD+Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

Taichi Nagahisa, Shintaro Yamaguchi, Shotaro Kosugi, Koichiro Homma, Kazutoshi Miyashita, Junichiro Irie, Jun Yoshino, Hiroshi Itoh

Research output: Contribution to journalArticlepeer-review

Abstract

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

Original languageEnglish
Article numberbqac023
JournalEndocrinology (United States)
Volume163
Issue number4
DOIs
Publication statusPublished - 2022 Apr 1

Keywords

  • GLP-1
  • NAD
  • NAMPT
  • intestine
  • obesity
  • postprandial glucose metabolism

ASJC Scopus subject areas

  • Endocrinology

Fingerprint

Dive into the research topics of 'Intestinal Epithelial NAD+Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice'. Together they form a unique fingerprint.

Cite this