Resumen de Nicotinamide effects on adiposity, energy metabolism, inflammation and atherosclerosis in mice
Background and hypothesis Adipose tissue dysfunction is a hallmark of obesity and is frequently associated with distorted metabolic homeostasis, cardiovascular and chronic, low-grade inflammatory diseases. Several recent studies point to pharmacological and/or nutritional health initiatives targeting adipose tissue being a promising approach to obesity prevention. In this regard, nicotinamide adenine dinucleotide (NAD)+ precursors, such as nicotinamide riboside and mononucleotide nicotinamide has been proven beneficial in increasing energy metabolism and preventing body weight gain in vivo. However, their impact on disturbed white adipose tissue (WAT) physiology or in alleviating chronic inflammation, which frequently accompanies obesity, was not addressed in any of these studies. In addition to the above-mentioned NAD precursors, nicotinamide (NAM) is also a physiological precursor of NAD+. However, its contribution in boosting energy metabolism and body weight gain still remains largely unknown. Although a growing body of evidences also supports a role for NAM as an anti-oxidant and anti-inflammatory agent both in vitro and in vivo, its potential contribution in preventing atherosclerosis, which is one of the main mechanisms involved in cardiovascular disease, has not previously analyzed.
Aims The aim of this study was to investigate the effect of NAM supplementation in (1) preventing weight gain and adiposity and (2) improving chronic inflammation in appropriate mouse models of obesity (diet-induced obesity -DIO- mice) and atherosclerosis (Apolipoprotein(Apo)E-deficient mice).
Results NAM administration to mice was provided orally via tap water at libitum. Its administration was shown palatable, safe and well tolerated at doses below 1%.
NAM supplementation, at the highest dose used (1%) (NAM HD-treated mice), prevented body weight gain, with the latter being repeatedly accompanied by reduction in fat accumulation in different regional depots and in hepatic steatosis. Such anti-adiposity effect of NAM was associated to an [i] increased global energy expenditure, [ii] enhanced promotion of browning in subcutaneous (sc)WAT, as revealed by elevations in the relative mRNA and protein abundance of the uncoupling protein (Ucp)-1, and [iii] elevation of NAD+ and NAD/NADH ratio in scWAT of NAM HD-treated, DIO mice. Notably, the AMP content was significantly elevated in scWAT of NAM HD-treated, DIO mice. Also, the NAD+/NADH ratio was directly related to the AMP/ATP ratio. Overall, these data suggest a situation of energy demand in scWAT from NAM HD-treated mice that was concomitant with an increase in the protein abundance of the active (phosphorylated) form of AMP-activated kinase in this tissue.
NAM supplementation also prevented inflammation and atherosclerosis development in ApoE-deficient mice. This was revealed by increased circulating concentrations of interleukin (IL-)10 and upregulation of relative mRNA of Il10 in both adipose and aortic tissues, suggesting a switch to anti-inflammatory M2 macrophages. This phenotype was accompanied by a reduction in atherosclerosis in these mice. In addition, non-HDL of NAM-treated, ApoE-deficient mice were less prone to oxidation than those from untreated mice, being this effect at least partly provided by a direct anti-oxidant action of NAM. Conclusions Dietary supplementation with NAM to mice prevented body weight gain and adiposity by boosting energy expenditure, with this being mainly attributed to browning and energy demand induction in scWAT. NAM also promoted anti-inflammatory and anti-oxidant actions in target tissues, including aorta, where it did protect against atherosclerosis development.
