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5-amino-1MQ

Obesity may significantly impact one’s quality of life, as it can negatively affect independent movement and exercise. While this condition can cause physical and emotional problems, it can also increase one’s risk for deadly diseases such as heart problems, diabetes, cancer, stroke, and non-alcoholic liver failure. Unfortunately, once you become obese, this condition is extremely difficult to reverse or even treat effectively. This is because obesity affects the body’s ability to break down fat stores and use it as a source of energy. In fact, even drugs that have been designed to boost fat breakdown may be ineffective. Therefore, body fat accumulates over time and becomes very challenging to remove without surgical intervention.

Recently, a new breakthrough may help patients with this severe form of obesity achieve healthier weight. The NNMT inhibitor 5-amino-1-methylquinoline or 5-amino-1MQ has been shown to reduce the production of the enzyme nicotinamide N-methyltransferase (NNMT), a regulator of energy homeostasis in adipose tissue (a type of fat used for energy storage). This mechanism could shrink white adipose tissue and dramatically reduce weight without the need for limiting calorie intake.

Overall Health Benefits of 5-amino-1MQ

  • Produces dramatic weight loss [1-8]
  • Fights inflammation [9-14]
  • Combats various cancer types [15-29]
  • Enhances aged muscle regeneration [30]
  • Lowers cholesterol and blood sugar levels [2]

Proven Health Benefits of 5-amino-1MQ

Produces Dramatic Weight Loss

Evidence suggests that by shrinking white adipose tissue, 5-amino-1MQ can significantly reduce weight and improve body composition:

  • In U.S. Veterans military service members, administration of 5-amino-1MQ resulted in significant weight loss without any adverse side effects. [1]
  • In diet-induced obese mice maintained on a high-fat diet, administration of NNMT inhibitor significantly reduced body weight and white adipose tissue mass, and decreased the size of adipocyte cell (a cell specialized for fat storage) without any observable adverse effects. [2-3]
  • Administration of NNMT inhibitor in mice on a high fat diet (HFD) protected against fat accumulation compared with controls. [4]
  • Studies also show that NNMT is increased 2-fold in subcutaneous and abdominal adipose tissue of type 2 diabetic men and women compared to healthy controls, suggesting that administration of NNMT inhibitors may reduce body fat. [5-7]
  • A cell study found that 5-amino-1MQ prevented lipogenesis (fat formation). [8]

Fights Inflammation

Evidence suggests that the enzyme NNMT is highly associated with inflammatory conditions and related injuries, suggesting that NNMT inhibitors like 5-amino-1MQ may have an anti-inflammatory role:

  • Significantly increased levels of NNMT have been observed in the lungs and skeletal muscle of patients with chronic obstructive pulmonary disease (COPD) with muscle wasting. [9-10]
  • Increased NNMT levels were also seen in the skeletal muscle of patients with various forms of muscular abnormalities. [11]
  • Experimental studies in mice also found an increase in NNMT levels after drug-induced liver injury. [12-13]
  • A study found that NNMT production is the body’s protective compensatory response to injury, resulting in inflammatory states. [14]

Combats Various Cancer Types

A number of high quality studies also suggest that high levels of NNMT are strongly linked with the development of various types of cancer, suggesting a potential therapeutic role for NNMT inhibitors:

  • NNMT levels are significantly increased in primary glioblastoma tumors (aggressive brain tumors) compared to normal human brain samples. [15]
  • Enhanced NNMT production is also increased in human papillary thyroid cancer cell lines. [16]
  • In renal clear cell carcinoma, NNMT production is also significantly increased. [17]
  • In human bladder cancer, NNMT was found to be a major regulator of cell migration. [18]
  • The NNMT protein is also increased in gastric cancers. [19-20]
  • NNMT is also identified as a novel serum tumor marker for human colorectal cancers and oral squamous cell carcinoma. [21-22]
  • NNMT knockdown (NNMT gene loss) decreased proliferation and migration of bladder cancer cells. [23]
  • NNMT knockdown also inhibited the proliferation and/or metastasis of kidney cancer cells, pancreatic cancer cells, and oral squamous carcinoma. [24-26]
  • In non-small-cell lung cancer cells, inhibition of NNMT production resulted in suppression of tumor growth. [27]
  • Higher levels of NNMT in tumor tissues are associated with lower overall survival rates in cancer patients, suggesting that NNMT inhibitor administration may help improve survival. [28]
  • In human oral cancer cell line, administration of NNMT inhibitor dramatically reduced cancer cell growth and reproduction. [29]

Enhances Aged Muscle Regeneration

5-amino-1MQ and other NNMT inhibitors have the potential to help older people with age-related muscle weakness become fitter and stronger, thus allowing them to live an active lifestyle.

A 2019 study published in Biochem Pharmacology found that NNMT inhibitor administration in a group of old mice with senescent muscle stem cells enhanced aged muscle regeneration. [30] In this study, old mice (24 months) underwent barium chloride injection to induce an acute muscle injury. A group of mice were then treated with saline (control) and another group treated with low and high dose of NNMT inhibitor (5 and 10 mg/kg) for 1 week.

Results revealed that regeneration of muscle stem cells (muSCs) were faster in NNMT inhibitor-treated mice, supporting nearly 2-fold greater muscle cell fiber cross-sectional area (CSA) measurements compared with control. In addition, NNMT inhibitor-treated mice exhibited greater contractile function, which is indicative of improved muscle function. These results provide the first clear evidence that NNMT inhibitors can be considered as a therapeutic option for age-related muscle wasting and weakness by rescuing muscle stem cell function and improving skeletal muscle regenerative capacity.

Lowers Cholesterol and Blood Sugar Levels

As a NNMT inhibitor, 5-amino-1MQ’s weight-reducing effects could produce additional benefits such as improvement of cholesterol profile and reduction of blood sugar levels.

A 2018 study published in the Dibetes Journals investigated the effects of NNMT inhibitor in diet-induced obese (DIO) mice maintained on a high-fat diet. [2] During the study period, the researchers assessed different health parameters such as fat mass, oral glucose tolerance, fat cell levels, and circulating lipids.

Interestingly, results showed that systemic treatment of DIO mice with a potent NNMT inhibitor dramatically reduced body weight, fat mass, fat cell size, blood sugar levels, and plasma cholesterol levels. In addition, researchers observed that the treatment did not alter food intake nor produce any adverse side effects. These results suggest that NNMT inhibitors can help improve body composition as well as cholesterol and blood sugar levels.

References:

  1. Available from https://apps.dtic.mil/dtic/tr/fulltext/u2/1059191.pdf.
  2. Available from https://diabetes.diabetesjournals.org/content/67/Supplement_1/115-LB.
  3. Neelakantan H, Vance V, Wetzel MD, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol. 2018;147:141–152. doi:10.1016/j.bcp.2017.11.007.
  4. Kraus D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014; 508:258–262.
  5. Kannt A, et al. Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance. Diabetologia. 2015; doi: 10.1007/s00125-014-3490-7.
  6. Liu M, et al. Serum N(1)-Methylnicotinamide Is Associated With Obesity and Diabetes in Chinese. J Clin Endocrinol Metab. 2015; 100:3112–3117.
  7. Pissios P. Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme. Trends Endocrinol Metab. 2017;28(5):340–353.
  8. Neelakantan H, Wang HY, Vance V, Hommel JD, McHardy SF, Watowich SJ. Structure-Activity Relationship for Small Molecule Inhibitors of Nicotinamide N-Methyltransferase. J Med Chem. 2017;60(12):5015–5028.
  9. Kim HC, et al. Expression and functional significance of nicotinamide N-methyl transferase in skeletal muscles of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010; 181:797–805.
  10. Savarimuthu Francis SM, et al. Genes and gene ontologies common to airflow obstruction and emphysema in the lungs of patients with COPD. PloS One. 2011; 6:e17442.
  11. Zhang H, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016; 352:1436–1443.
  12. Sternak M, et al. Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse. Pharmacol Rep PR. 2010; 62:483–493.
  13. Fedorowicz A, et al. Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension. Respir Res. 2016; 17:108.
  14. Jakubowski A, et al. 1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α. Int Immunopharmacol. 2016; 31:98–104.
  15. Markert JM, et al. Differential gene expression profiling in human brain tumors. Physiol Genomics. 2001;5:21–33.
  16. Xu J, et al. Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells. J Clin Endocrinol Metab. 2003;88:4990–4996.
  17. Yao M, et al. Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol. 2005;205:377–387.
  18. Wu Y, et al. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–6689.
  19. Jang JS, et al. The differential proteome profile of stomach cancer: identification of the biomarker candidates. Oncol Res. 2004;14:491–499.
  20. Lim BH, et al. Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification. Exp Mol Med. 2006;38:455–465.
  21. Roessler M, et al. Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:6550–6557.
  22. Sartini D, et al. Nicotinamide N-methyltransferase upregulation inversely correlates with lymph node metastasis in oral squamous cell carcinoma. Mol Med Camb Mass. 2007;13:415–421.
  23. Wu Y, et al. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–6689.
  24. Yu T, et al. Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2015;35:710–721.
  25. Tang SW, et al. Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells. Carcinogenesis. 2011;32:138–145.
  26. Pozzi V, et al. RNA-mediated gene silencing of nicotinamide N-methyltransferase is associated with decreased tumorigenicity in human oral carcinoma cells. PloS One. 2013;8:e71272.
  27. Bach DH, Kim D, Bae SY, et al. Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells. Mol Ther Nucleic Acids. 2018;11:455–467. doi:10.1016/j.omtn.2018.03.011.
  28. Bae S.Y., Park H.J., Hong J.Y., Lee H.J., Lee S.K. Down-regulation of SerpinB2 is associated with gefitinib resistance in non-small cell lung cancer and enhances invadopodia-like structure protrusions. Sci. Rep. 2016;6:32258.
  29. Gao Y, Van haren MJ, Moret EE, et al. Bisubstrate Inhibitors of Nicotinamide -Methyltransferase (NNMT) with Enhanced Activity. J Med Chem. 2019;62(14):6597-6614.
  30. Neelakantan H, Brightwell CR, Graber TG, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol. 2019;163:481-492.

 

 

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