Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

Abstract

SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

Phenotypic, hormonal, and clinical characteristics of equine endocrinopathic laminitis

“…Insulin sensitivity appears to decline with age in horses. 36,37 Given that this also occurs in other species, 38,39 it is unknown why this outcome was not evident in the current study, but concurrent PPID in some cases could have been a confounding factor. However, basal/resting insulin concentration is an insensitive measure of insulin dysregulation in horses, 40 and it is probable that normal resting insulin concentrations were present in some animals with insulin dysregulation in the current study, which would have affected the ability to accurately assess the relationship between insulin sensitivity and age.…”

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…344 The overexpression of Nmnat3 efficiently boosts NAD + in a variety of murine tissues, which significantly suppresses the ROS generation, and protects from aging-related insulin resistance. 360 Overexpression of G6PD promotes NADPH production, preventing tissue from oxidative damage to improve mice health span. 361 NAD + also regulates oxidative stress in cellular senescence by regulating sirtuins and PARPs.…”

Keeping the balance in NAD metabolism

“…For example, Nmnat3 -/mice are viable and the absence of an NMNAT3 appears to affect metabolic functions rather in the cytosol than in mitochondria (38). NAD levels in skeletal muscle, which are elevated in transgenic Nmnat3 mice (39), are hardly affected in Nmnat3 -/mice (40). These findings suggest alternative mechanisms to compensate for the lack of NMNAT3.…”