Nicotinamide Protects Against Diet‐Induced Body Weight Gain, Increases Energy Expenditure, and Induces White Adipose Tissue Beiging

Abstract

Scope Interventions that boost NAD+ availability are of potential therapeutic interest for obesity treatment. The potential of nicotinamide (NAM), the amide form of vitamin B3 and a physiological precursor of nicotinamide adenine dinucleotide (NAD)+, in preventing weight gain has not previously been studied in vivo. Other NAD+ precursors have been shown to decrease weight gain; however, their impact on adipose tissue is not addressed. Methods and results Two doses of NAM (high dose: 1% and low dose: 0.25%) are given by drinking water to C57BL/6J male mice, starting at the same time as the high‐fat diet feeding. NAM supplementation protects against diet‐induced obesity by augmenting global body energy expenditure in C57BL/6J male mice. The manipulation markedly alters adipose morphology and metabolism, particularly in inguinal (i) white adipose tissue (iWAT). An increased number of brown and beige adipocyte clusters, protein abundance of uncoupling protein 1 (UCP1), mitochondrial activity, adipose NAD+, and phosphorylated AMP‐activated protein kinase (P‐AMPK) levels are observed in the iWAT of treated mice. Notably, a significant improvement in hepatic steatosis, inflammation, and glucose tolerance is also observed in NAM high‐dose treated mice. Conclusion NAM influences whole‐body energy expenditure by driving changes in the adipose phenotype. Thus, NAM is an attractive potential treatment for preventing obesity and associated complications.

Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling

“…Nicotinamide is generally known to decrease cytokine production and inflammatory responses in various cell types and tissues ( Mendez-Lara et al., 2021 ; Rehman et al., 2021 ; Ungerstedt et al., 2003 ; Zheng et al., 2019 ); however, the mechanism by which NAM alters adaptive T cell immunity is unknown but is crucial to understand because this is a widely used human supplement. For example, it is unclear if NAM specifically affects naive T cell transition into effector T cells, effector function itself, or subsequent responses.…”

“…Two studies demonstrated that NAM mediates chemopreventive effects by boosting immune cell cytokine production in different models of murine cancers ( Buque et al., 2020 ; Scatozza et al., 2020 ). Conversely, other studies showed that NAM supplementation reduced inflammation protecting against high fat diet-induced inflammation ( Mendez-Lara et al., 2021 ; Mitchell et al., 2018 ), an Experimental Autoimmune Encephalitis (EAE) model ( Kaneko et al., 2006 ), and pulmonary injury caused by ischemia/reperfusion in rats ( Su et al., 2007 ).…”

“…Several studies have reported the in vivo anti-inflammatory effect of NAM ( Mendez-Lara et al., 2021 ; Mitchell et al., 2018 ; Su et al., 2007 ). Consistent with these findings, NAM was shown to decrease inflammation and CD4 + T cell infiltration in an Experimental Autoimmune Encephalitis (EAE) model ( Kaneko et al., 2006 ); however, recent work demonstrated how NAM enhances T cell response and cytokine production, mediating chemopreventive effects in different models of murine cancers ( Buque et al., 2020 ; Scatozza et al., 2020 ).…”

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

“…Organ fibrosis is characterized by excess deposition of extracellular matrix proteins. Administration of NA, NAM, and NR attenuates experimental liver fibrosis [ 14 , 121 , 122 , 123 , 124 ], potentially indicating that an insufficient NAD+ supply may underlie organ fibrosis. Similar favorable effects could be conceivably suggested for NAD+-increasing interventions aiming to directly combat myocardial fibrosis.…”

“…Accordingly, many studies have revealed that dietary administration of NAD+ precursors, such as tryptophan, nicotinic acid (NA, also termed niacin), nicotinamide (NAM), and nicotinamide riboside (NR), and its phosphorylated form, nicotinamide mononucleotide (NMN), efficiently raises the tissue NAD+ content in rodents and humans [ 8 , 9 ]. In particular, NAM, NMN, and NR administration has been reported to prevent obesity and improve glucose tolerance in mice [ 10 , 11 , 12 , 13 , 14 ] and favorably influenced fatty liver by reducing oxidative stress and inflammation in aged, diet-induced obese mice [ 15 ]. Conceivably, NAD+ precursors may protect the cardiovascular system [ 6 , 16 ].…”