How does 5-Amino-1MQ reduce fat cell size, increase fat metabolism and promote weight loss?

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NNMT Inhibitor Caused Weight Loss and Reduced Adipose Tissue Mass in Mice.​

"Consistent with these results, histological analysis of the EWAT [epididymal white adipose tissue] from treated DIO mice had

1. "> 30% decrease in adipocyte size...

2. > 40% decrease in adipocyte volume (data not shown) compared to control DIO mice...

3. Plasma lipid-profile measurements showed that the total cholesterol levels were ~30% lower in treated DIO mice relative to control DIO mice...

4. DIO mice treated with the NNMT inhibitor showed a weight loss of 2.0 ± 0.6 g (~5.1% weight loss from baseline measures). Food intake remained the same between the groups suggesting the weight loss effect is primarily related to altered metabolism...

5. Treatment of DIO mice with the NNMT inhibitor resulted in a substantial ~35% decrease in the mass and size of the EWAT [epididymal white adipose tissue] compared with the control DIO mice..."

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Decreased Fat Cell Size, Reduced Body Weight, and Lowered Cholesterol in Mice.​

“There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis.

To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors.

  • Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays.
  • Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD+) salvage pathway enzymes… Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD+ salvage pathway.
  • NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD+ and S-(5′-adenosyl)-L-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels.
  • Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects.
These results support development of small molecule NNMT inhibitors as therapeutics to reverse diet-induced obesity and validate NNMT as a viable target to treat obesity and related metabolic conditions. Increased flux of key cellular energy regulators, including NAD+ and SAM, may potentially define the therapeutic mechanism-of-action of NNMT inhibitors.”

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Mechanism of 5-Amino-1MQ Inside of Fat Cell Identified:​

"NNMT is a cytosolic enzyme with a newly identified role in modulating cellular energy homeostasis by jointly regulating nicotinamide (NA) and S-(5′-adenosyl)-L-methionine (SAM) flux within the critical intracellular nicotinamide adenine dinucleotide (NAD+) salvage pathway and methionine cycle, respectively.[15] NNMT expression is upregulated in the white adipose tissue (WAT) of obese and diabetic mice[12] and has significantly higher activity in the WAT compared to its activity in the brown adipose tissue, liver, and lungs of diet-induced obese mice."

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"...plasma levels of the NNMT reaction product 1-methylnicotinamide (1-MNA) correlate with adipose NNMT expression, individuals’ body mass index (BMI), and waist circumference, suggesting the target to be clinically relevant."

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"NNMT protein expression was found to be ~37-fold higher in the adipocytes (day 9) vs pre-adipocyte. Similarly, 1-MNA levels normalized to total cellular protein were ~7.5-fold higher in adipocytes compared to preadipocytes, suggesting relatively higher activity of the NNMT enzyme in the fully differentiated adipocytes. NNMT inhibition using 5-amino-1MQ in both the pre-adipocytes and the adipocytes resulted in significant reduction in the intracellular levels of 1-MNA... NNMT inhibitors are selective and do not impact related methyltransferases or enzymes in the NAD+ salvage pathway."



Enlarged, Inflammatory Fat (Adipose) Found In Obesity:​

“Adipose Tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone-marrow derived immune cells that signal via production of cytokines and chemokines.”

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Organ Damage Caused By Enlarged Adipose Cells: "Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity." (2)

"Obesity is a major public health problem around the world that is linked to severe comorbid disease conditions, physical impairment, high mortality rates, and compromised quality of life. Obesity is characterized by the buildup of excessive body fat and extreme dysregulation in whole-body energy expenditure, glucose, hormone, and lipid homeostasis that typically present as adverse metabolic disorders. Additionally, the physiological, metabolic, and psychological changes that accompany obesity are major factors in the development of type 2 diabetes (T2D), cardiovascular disease (CVD) (e.g., coronary heart disease, dyslipidemia, hypertension), stroke, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), osteoarthritis, sleep apnea, and several obesity-linked cancers (e.g., colorectal, breast, kidney, prostate). (1)
 
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