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Nicotinamide n methyltransferase knockdown protects against diet induced obesity – Editorial Summary

This modification enhances their binding affinity to complementary sequences and their resistance to the action of nucleases.

Ethan Walker
Sunday, March 27, 2016
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  • Biotechnology and Molecular Medicine, A.

  • Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. PDF kb.

  • Chen, H.

1. Introduction

Nucleic Acids Res. Additionally, NNMT is emerging protcets a new molecular target in fatty liver diseases. We asked whether NNMT regulates energy expenditure in a cell-autonomous manner. The levels of histone methylation were normalized to total H3 expression. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D.

Recently viewed grants:. The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Interferon regulatory factors are transcriptional regulators of adipogenesis. Metabolism: An energizing flux. JunaidDavid B. Identification of novel targets for treating and preventing obesity and diabetes is urgently needed.

  • Ethics declarations Competing interests B. Endocrinology

  • Therefore, more studies are needed in the future to further clarify the roles of NNMT in energy metabolism and the related mechanisms.

  • Shepherd, P.

  • Influence of threonine metabolism on S -adenosylmethionine and histone methylation.

  • Conclusion Evidence has shown that NNMT plays important roles in obesity and T2D and that NNMT inhibition significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels.

Pirnes-Karhu and T. Svenson, K. Hepatology 52— Share This Paper. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. Skip to main content Thank you for visiting nature. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism.

Rodgers J. Lee Y. Furthermore, NNMT overexpression has been shown to reduce the sensitivity of breast cancer cells to adriamycin- and paclitaxel -induced apoptosis by increasing SIRT1 stabilization and activity, and there is also evidence that targeting NNMT or downstream SIRT1 could improve the efficacy of breast cancer chemotherapy [ 82 ]. Neuronal PTP1B regulates body weight, adiposity and leptin action.

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Abstract In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes 1. SAM provides substrate propylamine for polyamine metabolism and donates a methyl group for histone methylation. Kraus, D. Show results from All journals This journal.

  • Published in the April 10 issue of the journal Naturethe new findings show that reducing the amount of nicotinamide N-methyltransferase NNMT protein in fat and liver dramatically reduces the development of obesity and diabetes in mice.

  • Molecular changes associated with metabolic reprogramming are required to meet the energy demands of cancer cells and to support tumor growth. In addition to oligonucleotide therapeutics, some small-molecule NNMT inhibitors have been reported recently [ 56 — 59 ] and several have shown effectiveness in the prevention or treatment of obesity and T2D in vitro [ 6061 ] or in preclinical animal models [ 105862 ], validating NNMT as a pharmacological drug target.

  • Methods Mol. In a new study, researchers have managed to completely block the development of obesity.

  • Yang X, et al. Early evidence of the association between NNMT and obesity was observed in metabolomic works, of which the results show that the MNA levels in human urine are positively correlated with the body mass index BMI [ 2021 ].

  • More than one-third of the U. In Aim 1, we will use pharmacological and genetic approaches to further elucidate the roles of NNMT in regulating energy expenditure.

Sirt1 regulates aging and resistance to oxidative stress in the heart. In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes 1. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity 2. The American Journal of Human Genetics.

Nature Figure 3: NNMT regulates energy expenditure. More Filters. Some features of the site may not work correctly.

PubMed Google Scholar. Fried for protocols for FAS activity measurements; and P. BMC Psychiatry View 5 excerpts, cites background and methods. Highly Influenced. KrausQ.

Associated Data

View author publications. Share this grant: : :. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. Name University of California Irvine.

Wu C, et al. On the contrary, NNMT overexpression increases hepatocyte glucose output, G6pc expression, and Pck1 expression in primary hepatocytes. Fried for protocols for FAS activity measurements; and P. Although the current evidence is very promising, there are still some knowledge gaps that should be addressed to further clarify the exact mechanisms linking NNMT to obesity and T2D and to develop clinical drugs targeting NNMT.

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Korhonen, T. Results Citations. Interferon regulatory factors are transcriptional regulators of adipogenesis. About this article Cite this article Kraus, D. Shepherd, P. Pirinen and T.

Development of fluorescence polarization-based competition assay for nicotinamide N-methyltransferase. Diagnosis and classification of diabetes mellitus. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. Tomida M.

Sample size knockdoown chosen based on results from pilot studies and our extensive experience in investigating metabolic physiology in mice. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yang Q, et al. Semenkovich and S. Journal of Sports Sciences.

Histone methylation: a dynamic mark in health, disease and inheritance. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Metabolism and epigenetic interplay in cancer: regulation and putative therapeutic targets. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.

Identification of novel targets for treating and preventing obesity and diabetes is urgently needed. Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Accepted : 03 March Sartini, D. Adipose tissue as a source of nicotinamide N -methyltransferase and homocysteine.

1. Crosstalk between cellular metabolism and epigenetic regulation

Cell metabolism. PowerPoint slide for Fig. Specifically, hepatic expression of NNMT improves lipid parameters, while high adipose expression of NNMT correlates with adiposity and insulin resistance [ 32 ]. Houtkooper, R. Yaguchi, H.

View all the latest top news in the environmental sciences, or browse the topics below:. Aryal for assistance with real-time qPCR. You can also search for this author in PubMed Google Scholar. Pulinilkunnil, T. Nucleic Acids Res. CAS Google Scholar. Beth Israel Deaconess Medical Center.

Obesity-related diseases including heart disease, stroke, type 2 diabetes, and cancer are a leading cause Salek, R. Adrenergic regulation of AMP-activated protein kinase in brown adipose tissue in vivo. Genomics 85— Tax calculation will be finalised during checkout. Journal information About the Journal Awards Editorial policies.

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Karppinen, A. Received Mar 8; Accepted Jul In glioblastoma, inhibition of NNMT increases intracellular levels of nicotinamide, leading to radiosensitization [ 63 ]. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. However, it is noteworthy that ten oligonucleotide drugs have been officially approved by FDA as of January [ 55 ], which means that the technological obstacles for oligonucleotide therapeutics are being solved step by step and the development of oligonucleotide drugs targeting NNMT is still a promising method for the prevention or treatment of obesity and related T2D in the future.

NNMT: a bad actor in fat makes good in liver. Annual Review of Animal Biosciences. Share this article Share with email Share with twitter Share with linkedin Share with facebook. The Journal of Pathology. Gong F 5. Stat3 up-regulates expression of nicotinamide N-methyltransferase in human cancer cells.

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Zhou Q. Bromberg A. Journal of Cancer Research and Clinical Oncology. Haigis M.

View 5 excerpts, cites background and methods. Mouse phenome database. Correspondence to Qin Yang or Barbara B. Wu, C. Metabolism

Salek, R. PDF kb. Methods Mol. Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Kong and Alexander S. Share this grant: : :.

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Some features of the site may not work correctly. The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis. Gong and Ya-chin Wang and Y. Insulin imbalance may not be the only cause of the onset of diabetes. Asara, Odile D. Download citation.

More than one-third of the U. We thank R. Insulin imbalance may not be the only cause of the onset of diabetes. More Filters.

Circ Res. SAM regulates polyamine flux by providing substrates and modulating histone methylation. Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state. We sought to determine whether the leanness with Nnmt knockdown is due to reduced energy intake or increased energy expenditure. NNMT regulates the expression of CAF markers and pro-tumorigenic cytokines by mediating genome-wide DNA methylation changes and also through the hypomethylation of repressive chromatin marks.

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Buy or subscribe. Trials 27— About this article Cite this article Kraus, D.

N1-methylnicotinamide MNAM as a guardian of cardiovascular system. Published online Jul Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Elevated N-methyltransferase expression induced by hepatic stellate cells contributes to the metastasis of hepatocellular carcinoma via regulation of the CD44v3 isoform.

News Article. Obesity-related diseases including heart disease, stroke, type 2 diabetes, and cancer are a leading cause Yang, X. Rodgers, J. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Rent or Buy article Get time limited or full article access on ReadCube. Abstract In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes 1.

  • DimetHarshini NeelakantanKehinde O.

  • Pulinilkunnil TC 5. The glucose fatty-acid cycle.

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  • The acetylated products including N 1 -acetylspermine, N 1N 12 -diacetylspermine, and N 1 -acetylspermidine, are either oxidized by PAO or excreted intact in urine. Gong F 5 .

N 1 -methylnicotinamide treatment promoted diacetylspermine jethyltransferase from adipocytes in a dose-dependent manner Fig. Grubb, S. Svenson, K. NNMT plays a positive role in the muscle fiber repair process as its overexpression in myoblasts elicits significant proliferation and migration activities. Weinshilboum Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Recently, nicotinamide N-methyltransferase NNMT has been emerging as a new mechanism-of-action target in treating obesity and associated T2D.

Cancer Res. KrausQ. Rodgers, J. M and S. Banks and L. Paper Mentions. The applicant identified an enzyme called nicotinamide N-methyltransferase NNMT as a novel regulator of energy expenditure.

DimetHarshini NeelakantanKehinde O. Funding Agency. Obesity-related diseases including heart disease, stroke, type 2 diabetes, and cancer are a leading cause

Data from transfection experiments show that NNMT activity promotes the proliferation, migration, and survival of cancer cells [ 6061 ]. First, MNA is not stable in in vivo. Trends in biochemical sciences. Author Contributions Q. Martinez-Chantar M.

Activation of nicotinamide N-methyltransferase gene promoter by hepatocyte nuclear factor-1beta in human papillary thyroid cancer cells. Genome Biol. Methylgransferase Jan Metabolism and epigenetic interplay in cancer: regulation and putative therapeutic targets. Changes in one-carbon metabolism can modulate gene expression by inducing changes in the histone methylation of key histone marks, such as H3K4me3 [ 2021 ].

Frontiers in Physiology. Clinical Cancer Research. Nucleic acids research. Zhou Q.

Has PDF. Thank you for visiting nature. Zhang and Joseph T. Published : 09 April Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization.

Rabbit anti-acetylated lysine was from Cell Signaling Technology. Conclusion Molecular transducers closely interconnect metabolism and epigenetics by activating cell-specific transcriptional networks in response to environmental changes. Molecular Cell. Kannt et al. Nature Chemical Biology. Nature— Mohammad R.

Cell metabolism. Abstract In protectss and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes 1. Recently, this association has been confirmed by many reports. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. In contrast, liver Nnmt expression does not parallel the propensity for obesity Supplementary Fig.

  • Rodgers and E. Thank you for visiting nature.

  • However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Uimari, S.

  • Karppinen, A. Obesity-related diseases including heart disease, stroke, type 2 diabetes, and cancer are a leading cause

  • Retrieved August 24, from www. Related projects.

  • Nature Medicine.

Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy sgainst. Tax calculation will be finalised during checkout. UddinRashad R. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase Nnmt is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue WAT from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective… Expand. References 1 Shepherd, P. Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism.

Aging Albany NY ; 3 2 — Molecular Neurobiology Feed efficiency Total calorie intake was computed from the measured food intake during the second and third weeks of ASO treatment. Genetic Testing and Molecular Biomarkers. References 1.

  • References 1 Shepherd, P.

  • In fact, metabolic reprogramming, driven by the activation of oncogenes, the inactivation of tumor suppressor genes and alterations in metabolic enzymes, induces the modulation of histone- and DNA-modification enzymes, which in turn regulate the expression of metabolism-associated genes [ 55 ]. Pulinilkunnil, T.

  • USA— The proposal is highly innovative in the aspects of new discovery, novel mechanisms and comprehensive approaches.

  • Nicotinamide N -methyltransferase in non-small cell lung cancer: promising results for targeted anti-cancer therapy.

Semenkovich and S. Asara and O. Note: Content may be edited for style and length. Alhonen and P. Metabolic effects of nicotinamide administration in rats. Mouse liver nicotinamide N -methyltransferase: cDNA cloning, expression, and nucleotide sequence polymorphisms. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform.

Int J Mol Sci22 1126 May Close banner Close. Feed efficiency Total calorie intake was methyltrsnsferase from the measured food intake during the second and third weeks of ASO treatment. It has been demonstrated that NNMT overexpression significantly inhibits apoptotic cell death and correlates with sensitivity to chemotherapeutic drugs [ 79 ]. Ramsden D. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.

Semenkovich and S. QJM 98— Nature Med. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Biochem Pharmacol, 15 Nov Crystal structures of monkey and mouse nicotinamide N-methyltransferase NNMT bound with end product, 1-methyl nicotinamide. American Diabetes Association. SSAT was assayed by measuring the formation of acetylated spermidine in a reaction with 14 C-CoA and spermidine as co-substrates. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Mentch S.

A glycine N-methyltransferase knockout mouse model for humans with deficiency of this enzyme. Journal of Sports Sciences. Development of fluorescence polarization-based competition assay for nicotinamide N-methyltransferase. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Martinez-Chantar M.

Asara, Odile D. Metabolism: An energizing flux. Rodgers and E. Nature

Thus, body weight and fat gain were disproportionally low for the calorie intake in Nnmt -ASO-treated compared with control-ASO-treated mice. Feed efficiency deit expressed as the body weight gain divided by the total calorie intake between the start and the end of the food intake measurement However, to date, oligonucleotide therapeutics are still facing some technological obstacles, such as how to achieve efficient oligonucleotide delivery to target organs or tissues, how to overcome off-target interactions [ 49 — 52 ], and how to address the sequence- and chemistry-dependent toxicity and saturation of endogenous RNA processing pathways [ 5354 ].

Nature Reviews Molecular Cell Biology Ulanovskaya, O. Preclinical antitumor efficacy of the polyamine analogue N1, Ndiethylnorspermine administered by multiple injection or continuous infusion. Williams, A. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Metabolism

Evidence has shown that NNMT expression in white adipose tissue WAT is high in obesity-prone mice and low in obesity-resistant mice [ 23 — 25 ] and significantly correlates with the percent fat mass in diet-induced obese mice [ 26 ]. Molecular Neurobiology. Serum N 1 -methylnicotinamide is associated with obesity and diabetes in Chinese. The mice were acclimated in the metabolic chambers for 2 days before the experiments. Cell Metabolism. Nicotinamide-N-methyltransferase gene rs variant and migraine risk. DimetHarshini NeelakantanKehinde O.

Bhanot and L. View author publications. Related projects.

One of the main epigenetic processes regulated by co-substrates generated by cellular metabolism is histone methyltransferase knockdown modifications PTMsamong which, histone acetylation and methylation have been extensively documented in terms of response obedity metabolic changes [ 2 ]. Although a growing amount of information is revealing how different transcription factors might regulate NNMT expression in a tissue-specific manner, how these modulations translate into concerted tissue-specific gene regulation is a central question that remains unanswered. Nicotinamide N -methyltransferase knockdown protects against diet-induced obesity. NNMT inhibitors Because of its regulatory role in cellular epigenetics and metabolism, together with its well-accepted involvement in several human diseases, NNMT can be considered as a new potential pharmacological target in the treatment of a variety of metabolic disorders, cancers, and other pathologies [ 87 ].

Advanced search. Yang and D. Kong and Alexander S. Received : 25 January

Kim J. Alexander S. Wang Y. Reprints and Permissions. If the depressed oxygen consumption caused by NNMT overexpression indicates the depression of aerobic metabolism, the regulatory effect of NNMT on anaerobic metabolism might be reversed.

Preclinical antitumor efficacy of the polyamine analogue N1, Ndiethylnorspermine administered by multiple injection or continuous infusion. Abstract Background The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase. Figure 4.

  • Nature; : DOI:

  • NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels.

  • Comments By submitting a comment you agree to abide by our Terms and Community Guidelines.

  • Glucose transporters and insulin action—implications for insulin resistance and diabetes mellitus. BMC Psychiatry

Correspondence to Qin Yang or Barbara B. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Get the most important science stories of the day, free in your inbox. Close banner Close. Paper Mentions. Here we show, using DNA array analyses, that nicotinamide N -methyltransferase Nnmt is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue WAT from adipose-specific Glut4 -knockout or adipose-specific Glut4 -overexpressing mice with their respective controls. Adipose tissue as a source of nicotinamide N -methyltransferase and homocysteine.

Molecular Neurobiology Funding Agency. Banks, Joseph T. Banks and L. Preclinical antitumor efficacy of the polyamine analogue N1, Ndiethylnorspermine administered by multiple injection or continuous infusion.

Acetyl-CoA is an essential acetyl donor for protein acetylation, particularly histone acetylation carried out by histone acetyltransferases HATs [ 3 ]. These phenomena indicate that NNMT might promote anaerobic metabolism [ 81 ]. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Molecular Endocrinology.

Some features of the site may not work correctly. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Zhang and Joseph T. Highly Influenced. Body weight predicts Nicotinamide N-Methyltransferase activity in mouse fat. Beth Israel Deaconess Medical Center.

Riederer, M. More than one-third of the U. ASOs are short molecular strings of DNA, which can be designed to prevent the synthesis of specific proteins. Kobayashi, Y. Rent or Buy article Get time limited or full article access on ReadCube.

Progress in molecular biology and translational science. Sirt1 regulates aging and resistance to oxidative stress in the heart. Molecular Endocrinology. RNA-mediated gene silencing of nicotinamide N-methyltransferase is associated with decreased tumorigenicity in human oral carcinoma cells. Conclusion Molecular transducers closely interconnect metabolism and epigenetics by activating cell-specific transcriptional networks in response to environmental changes.

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