Ps-B11-3: The Role of Intestinal Nampt-Mediated Nad+ Biosynthesis in Whole-Body Energy and Glucose Metabolism

Abstract

The purpose of the present study was to test our hypothesis that intestinal nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) biosynthesis plays a pivotal role in whole-body energy and glucose metabolism. To this end, we generated a new mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. Under regular chow diet, deletion of intestinal epithelial NAMPT did not affect body weight gain, food intake, or whole-body energy expenditure, suggesting that intestinal epithelial NAMPT deficiency had no significant impacts on overall energy intake or expenditure. However, INKO mice displayed reduced early-phase insulin secretion and postprandial hyperglycemia, at least partly due to diminished glucagon-like peptide-1 (GLP-1) production. In addition, we found that diet-induced obese mice had impaired intestinal NAMPT-mediated NAD+ biosynthesis, associated with impaired GLP-1 production and whole-body glucose metabolism, similar to the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide, to INKO and diet-induced obese mice, restored ileal NAD+ levels and obesity-associated metabolic derangements, manifested by an impairment in GLP-1 production as well as postprandial hyperglycemia. Taken together, our study provides a new understanding of the role of intestinal NAMPT-mediated NAD+ biosynthesis in energy and glucose metabolism, and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia (Nagahisa, Yamaguchi et al. Endocrinology. 2022). A future study using INKO mice to investigate if diminished GLP-1 production is involved in obesity-associated hypertension is warranted.