Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans

Abstract

Context Elevating NAD+ levels systemically improves metabolic health, which can be accomplished via nicotinamide riboside (NR). Previously, it was demonstrated that NR supplementation in high fat diet (HFD)-fed mice decreased weight gain, normalized glucose metabolism and enhanced cold tolerance. Objective As brown adipose tissue (BAT) is a major source of thermogenesis, we hypothesize that NR stimulates BAT in mice and humans. Design and intervention HFD-fed C56BL/6J mice were supplemented with 400 mg/kg/day NR for 4 weeks and subsequently exposed to cold. In vitro primary adipocytes derived from human BAT biopsies were pretreated with 50 µM or 500 µM NR prior to measuring mitochondrial uncoupling. Human volunteers (45-65 years, BMI: 27-35 kg/m 2) were supplemented with 1000 mg/day NR for 6 weeks to determine whether BAT activity increased, as measured by [18F]FDG uptake via PET-CT (randomized, double blinded, placebo-controlled, cross-over study with NR supplementation). Results NR supplementation in HFD-fed mice decreased adipocyte cell size in BAT. Cold exposure further decreased adipocyte cell size on top of that achieved by NR alone independent of ex vivo lipolysis. In adipocytes derived from human BAT, NR enhanced in vitro norepinephrine-stimulated mitochondrial uncoupling. However, NR supplementation in human volunteers did not alter BAT activity or cold induced thermogenesis. Conclusions NR stimulates in vitro human BAT, however not in vivo BAT in humans. Our research demonstrates the need for further translational research to better understand the differences in NAD + metabolism in mouse and human.

Nicotinamide riboside supplementation confers marginal metabolic benefits in obese mice without remodeling the muscle acetyl-proteome

“…The current investigation examined the impact of NRS on skeletal muscle metabolism in middle-aged male mice subjected to chronic high-fat feeding. We did not perform extensive analysis of the liver and we did not study the effect of the supplement on other organ systems such as brown adipose tissue (BAT)—a prominent thermogenic tissue implicated in the NRS-mediated increase in energy expenditure ( Crisol et al., 2018 ; Nascimento et al., 2021 ; Yamaguchi et al., 2019 ). Additionally, insulin sensitivity assessments were based on GTTs and ITTs rather than the hyperinsulinemic-euglycemic clamp technique, which is recognized as the gold standard measure of muscle insulin action.…”

Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects

“…However, the evidence to prove its therapeutic effects against aging and aging-related diseases is relatively limited. Several studies have reported that oral administration of NR could improve exercise performance, alter body composition, and enhance brown adipose tissue activity ( 30 – 32 ). In elderly people, 1 g of NR administration for 21 days was found to alter the mitochondrial-associated transcriptome in skeletal muscle and the circulating inflammatory cytokine profile; however, physiological parameters, such as body weight, blood pressure, lipid profile, and glucose metabolism, remained unaffected ( 33 ).…”

Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species production

“…Our results indicate that reactive species overproduction can induce uncoupling that spares destructive oxidation of mitochondrial oxidative phosphorylation machinery. Nevertheless, in human subjects, NR had no impact on thermogenesis ( Nascimento et al, 2021 ), leaving the question open about how these findings can be translated to humans.…”

“…NAD + metabolism is linked to adipocyte differentiation (Luo et al, 2017;Ryu et al, 2018;Huang et al, 2020;Szanto and Bai, 2020;Szanto et al, 2021) Nicotinamide-riboside (NR) is an NAD + precursor that efficiently induces cellular NAD + levels and mitochondrial biogenesis (Canto et al, 2012). NR supplementation efficiently induced mitochondrial biogenesis in models of obesity (Canto et al, 2012;Jukarainen et al, 2016;Rappou et al, 2016;Jokinen et al, 2017;Asnani-Kishnani et al, 2019;Vannini et al, 2019;Nascimento et al, 2021), inflammatory diseases (Wu et al, 2022), Parkinson's (Brakedal et al, 2022), non-alcoholic fatty liver disease (Dall et al, 2021), and aging (Sun et al, 2021). The objective of this study was to assess the effects of NR on the induction of shift of differentiation of white adipocytes to beige adipocytes (beiging) in a human adipose tissue-derived mesenchymal stem cell (hADMSC) model.…”