Nicotinamide mononucleotide induces lipolysis by regulating ATGL expression via the SIRT1-AMPK axis in adipocytes

Imi, Yukiko; Amano, Reina; Kasahara, Nanaho; Obana, Yuichiro; Hosooka, Tetsuya

doi:10.1016/j.bbrep.2023.101476

Cited by 4 publications

(4 citation statements)

References 55 publications

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“…The study showed a decrease in the size of adipocytes in subcutaneous adipose tissue after NMN treatment. Furthermore, the treatment with NMN resulted in a significant upregulation of adipose triglyceride lipase (ATGL) expression in subcutaneous fat, which is in line with the observed alterations in fat mass and adipocyte size (Imi et al, 2023). These findings suggest that NAD + may exert beneficial effects on lipid profiles by modulating the expression of lipidmetabolizing enzymes.…”

Section: Mechanisms Linking Decreased Nad + Levels To Metssupporting

confidence: 73%

“…Meta-analyses have shown that supplementation with NAD + precursors, including NMN, nicotinamide riboside (NR), NA, and NAM, significantly reduces levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL), while concurrently increasing high-density lipoprotein levels ( Zhong et al, 2022 ). Imi et al ( Imi et al, 2023 ). Demonstrated that administration of NMN, an NAD + precursor, markedly reduced subcutaneous fat mass in mice fed a high-fat diet (HFD).…”

Section: Potential Mechanisms Linking Nnmt To Metsmentioning

confidence: 99%

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Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

Sun,

Zhu,

et al. 2024

Front. Pharmacol.

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Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

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Section: Mechanisms Linking Decreased Nad + Levels To Metssupporting

confidence: 73%

Section: Potential Mechanisms Linking Nnmt To Metsmentioning

confidence: 99%

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

Sun,

Zhu,

et al. 2024

Front. Pharmacol.

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“…33,34 Accepted wisdom posits that the two key enzymes, HSL and ATGL, govern lipolysis, and research suggests that SIRT-1, by modulating ATGL, could regulate lipolysis in adipocytes. 35 Numerous studies have demonstrated that LPS induces lipolysis and contributes to insulin resistance. 36,37 While increased lipolysis in obesity diminishes fat accumulation, it may exacerbate insulin sensitivity due to elevated free fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…Accepted wisdom posits that the two key enzymes, HSL and ATGL, govern lipolysis, and research suggests that SIRT‐1, by modulating ATGL, could regulate lipolysis in adipocytes 35 . Numerous studies have demonstrated that LPS induces lipolysis and contributes to insulin resistance 36,37 .…”

Section: Discussionmentioning

confidence: 99%

The effect of quercetin on adipogenesis, lipolysis, and apoptosis in 3T3‐L1 adipocytes: The role of SIRT1 pathways

Maleki,

Abdizadeh Javazm,

Dastghaib

et al. 2024

Obesity Science & Practice

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BackgroundLipotoxicity, caused by adipocyte triglyceride over‐accumulation, contributes to obesity‐related comorbidities such as hypertension, type 2 diabetes, coronary heart disease, respiratory dysfunction, and osteoarthritis. This study focuses on determining how sirtuin‐1 (SIRT‐1) mediates quercetin's (QCT) effect on 3T3‐L1 adipocytes. Key aspects of this study include preventing adipogenesis, inducing lipolysis, and stimulating adipocyte apoptosis.Methods3T3‐L1 adipocytes underwent treatment with varying QCT doses, lipopolysaccharide (LPS), and the SIRT‐1 inhibitor EX‐527, followed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide [MTT] assay for cell viability assessment. Furthermore, quantitative real‐time polymerase chain reaction measured mRNA expression levels of adipogenesis markers (fatty acid synthase [FASN] and peroxisome proliferator‐activated receptor gamma [PPARγ]), lipolysis markers (adipose triglyceride lipase [ATGL] and hormone‐sensitive lipase [HSL]), and apoptosis markers (B‐cell lymphoma2 [Bcl‐2], Bcl‐2 Associated ‐X‐protein [BAX] and Caspase‐3).ResultsThe data showed that LPS + QCT significantly reduced cell viability in a dose‐ and time‐dependent manner, unaffected by LPS + QCT + EX‐527. Treatment with LPS + QCT did not affect FASN and PPARγ expression but significantly increased ATGL and HSL mRNA expression compared with LPS alone. Interestingly, EX‐527 reversed the effects of LPS + QCT on lipogenesis and lipolysis markers completely. QCT enhanced apoptosis in a SIRT‐1 independent pattern.ConclusionThe data suggest that QCT suppresses adipogenesis while increasing lipolysis via SIRT‐1. However, QCT's effects on apoptosis appear to be independent of SIRT‐1. These findings provide further evidence for QCT's effects on adipocytes, particularly its interaction with SIRT‐1.

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Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism

Zhou,

Zhang,

Wang

et al. 2024

J Virol

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Flavivirus infection capitalizes on cellular lipid metabolism to remodel the cellular intima, creating a specialized lipid environment conducive to viral replication, assembly, and release. The Japanese encephalitis virus (JEV), a member of the Flavivirus genus, is responsible for significant morbidity and mortality in both humans and animals. Currently, there are no effective antiviral drugs available to combat JEV infection. In this study, we embarked on a quest to identify anti-JEV compounds within a lipid compound library. Our research led to the discovery of two novel compounds, isobavachalcone (IBC) and corosolic acid (CA), which exhibit dose-dependent inhibition of JEV proliferation. Time-of-addition assays indicated that IBC and CA predominantly target the late stage of the viral replication cycle. Mechanistically, JEV nonstructural proteins 1 and 2A (NS1 and NS2A) impede 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation by obstructing the liver kinase B1 (LKB1)–AMPK interaction, resulting in decreased p-AMPK expression and a consequent upsurge in lipid synthesis. In contrast, IBC and CA may stimulate AMPK by binding to its active allosteric site, thereby inhibiting lipid synthesis essential for JEV replication and ultimately curtailing viral infection. Most importantly, in vivo experiments demonstrated that IBC and CA protected mice from JEV-induced mortality, significantly reducing viral loads in the brain and mitigating histopathological alterations. Overall, IBC and CA demonstrate significant potential as effective anti-JEV agents by precisely targeting AMPK-associated signaling pathways. These findings open new therapeutic avenues for addressing infections caused by Flaviviruses. IMPORTANCE This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro . In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.

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Nicotinamide mononucleotide induces lipolysis by regulating ATGL expression via the SIRT1-AMPK axis in adipocytes

Cited by 4 publications

References 55 publications

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome

The effect of quercetin on adipogenesis, lipolysis, and apoptosis in 3T3‐L1 adipocytes: The role of SIRT1 pathways

Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism

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