Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

Abstract

The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD+ biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD+-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK–NAMPT–NAD+–SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD+ biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD+ biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.

RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine

“…Further supporting a role for SCD1 in the stimulus–secretion coupling chain in L cells, SCD1 inhibition was found to reduce the expression of genes related to glycolysis, as well as ATP and NADH production. These are processes that have previously been shown to affect L cell secretion [ 49 , 50 ]. In agreement, we found that Scd1 KD reduced the acute mitochondrial respiratory response as measured using the Seahorse assay.…”

NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota

“…Intestinal NAD+ biology plays an important role in intestinal homeostasis, and the administration of NMN, one of the NAD+ precursors, increases intestinal NAD+ biosynthesis and positively influences gut physiology in vivo [13] Furthermore, NAD+ precursors have been described as potent anti-inflammatory agents. In particular, intestinal inflammation may be rescued using NAD+-increasing approaches [9,14]. This beneficial effect may be elicited directly, as is the case with NA, through a direct interaction with the GPR109a receptor, which inhibits the immune activation of resident macrophages and protects against further inflammatory cell infiltration, or indirectly after their conversion into NAD+.…”