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Excess weight and obesity can be difficult to reverse or treat effectively. This can be due to changes in metabolism that reduce the ability of the body’s fat stores to break down and become available as a source of energy. As a result, people affected by excess weight and obesity may find it harder to lose weight over time regardless of diets, eating styles or activity patterns.As fat cells grow larger, they begin to overproduce an enzyme called NNMT. This enzyme acts to slow down fat cell metabolism (fat burning). This slowdown makes it harder for these cells to burn accumulating fat. As fat tissue grows and more NNMT is produced, greater amounts of hormones and pro-inflammatory signals are produced that are responsible for weight gain and other chronic diseases such as type 2 diabetes and cardiovascular disease.Researchers at the University of Texas discovered a molecule that blocks this metabolic slowdown in white fat cells caused by excess NNMT. By blocking this metabolic slowdown, they were able to increase the metabolism within the white fat cells. Researchers add that by inhibiting the NNMT enzyme, we can increase fat cell metabolism and reduce the size of white fat deposits. We lose weight because we are treating a root cause of obesity and related metabolic disease.
What exactly is NNMT? NNMT stands for nicotinamide N-methyltransferase. It is the culprit in this discussion. It is also a very important cytosolic enzyme which modulates cellular energy balance. To put it simply, it regulates nicotinamide and S-(5′-adenosyl)-L-methionine within a couple of intracellular pathways that deal with cellular energy regulation. How many of us have thought that as we age our metabolism just isn’t the same as it used to be? Or why can’t we lose the excess weight that has accumulated over time? What happens when this cellular energy balance becomes unbalanced?It becomes what is known as the domino effect; one thing leads to the next. In this case, excess weight can lead to increased NNMT enzyme which can lead to poor fat cell metabolism which then leads to increased fat cell mass (weight gain).Here is why we need to decrease the NNMT for weight loss. First, decreased NNMT means the fat cells won’t grow. Second, decreased NNMT means fat cell metabolism can be corrected. And third, decreased NNMT means we lose weight because the fat cells shrink.Blocking Metabolic Slowdown = Weight Loss So how do we block the metabolic slowdown (or inhibit NNMT) so weight loss can occur? Researchers used variations of methylquinolinium (MQ) to measure the effectiveness of blocking NNMT. Out of all the variations of MQ studied, 5-amino 1MQ came out on top as the most effective. 5-amino 1MQ is a small, selective membrane permeable molecule that blocks the NNMT enzyme. What made it even more effective is that it did not affect the activity of any other enzymes in the metabolic cycles which reduced the risks of any potential side-effects.5-amino 1MQ has shown promise in blocking NNMT to enhance fat cell metabolism and promote weight loss. Most people don’t know that NNMT has been implicated in a number of other diseases including osteoarthritis, metabolic disorders, cardiovascular disease, cancer, Parkinson's disease, kidney disease, and other neurovascular/neurological dysfunctions. 5-amino 1MQ or another variation could be promising to treat a variety of other diseases.Benefits of 5-amino 1MQ Can reverse diet-induced obesityCan treat related metabolic conditionsCan increase cellular energy regulatorsCan prevent lipogenesis (fat accumulation)Can increase NAD+and SAM concentrations in fat cellsCan regulate energy expenditure in fat cells
Overview:
5-amino-1MQ is a small molecule drug that functions to block the activity of an enzyme called nicotinamide N-methyltransferase (NNMT) [5]. Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of methyl group from the cofactor S-(5′-adenosyl)-L-methionine (SAM) to substrates such as nicotinamide (NCA), pyridine, and related analogues (e.g., quinoline, isoquinoline, 1,2,3,4-tetrahydroisoquinoline), directly regulating the detoxification of endogenous and exogenous drugs/xenobiotics by the formation of methylated metabolic products (1-methyl nicotinamide [1-MNA], methylated pyridines, and methylated related analogues) [5].Given its primary metabolizing function, NNMT is predominantly expressed in the liver, but significant levels of the enzyme are also present in other tissues, including adipose tissue, kidney, brain, lung, heart, and muscle [4]. Enhanced expression and enzymatic activity of NNMT has been linked to a number of chronic disease conditions, making it a significant and relevant target for drug development [4].For example, several studies have demonstrated a causal relationship between increased NNMT expression and enhanced cell proliferation/progression in a variety of cancer cell lines with potential implications for NNMT as a biomarker for cancer prognosis and a target for anticancer therapeutic development.NNMT expression has also been reported to be upregulated in patients with Parkinson’s disease, which is suggested to be linked to the production of neurotoxins such as N- methylpyridinium ions that underlie neurodegeneration. SAM-dependent methyltransferases represent a major class of biotransforming enzymes that catalyze the methylation of linked to the production of neurotoxins such as N-methylpyridinium ions that underlie neurodegeneration [5].View the depiction that describes effects of NNMT inhibitor on intracellular levels of NAD+ salvage pathways methionine cycle metabolites [2].
5-Amino-1MQ and Weight LossNicotinamide N-methyltransferase (NNMT) has been implicated in osteoarthritis, metabolic disorders, cardiovascular disease, cancer, kidney disease, and Parkinson’s disease [3]. Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes [4].Researchers are currently making an effort to develop drug candidates that specifically target NNMT and produce targeted reductions in white adipose tissue, leading to significant weight loss and improvements in obesity-linked comorbidities. Importantly, these drug candidates have shown attractive cellular permeability flux when tested in membrane transport assays and in cells.Studies in both animals and humans have shown that NNMT expression and activity was increased in obesity and related chronic metabolic conditions (for example, type-2 diabetes) [2] [4]. Knockdown of NNMT expression using an antisense oligonucleotide was reported to suppress body weight gain, reduce fat mass, and increases energy expenditure in mice fed high fat diet [2].While the underlying molecular mechanisms that link decreased NNMT activity to increased adipocyte metabolism are not well understood, NNMT may modulate intracellular metabolite turnover in the methionine−homo-cysteine cycle and/or the nicotinamide adenine dinucleotide (NAD+) synthesis pathway critical for cellular energy expenditure [2].Therefore, targeted small molecule inhibitors of the NNMT could be significantly beneficial as molecular probes for mechanistic investigations and for the development of therapeutics to treat metabolic and chronic diseases that are characterized by abnormal NNMT activity [2].NNMT inhibition increases intracellular concentrations of NAD+ and SAM in differentiated adipocytes. Diet-induced obesity (DIO) mice had over a 30% decrease in adipocyte size and over a 40% decrease in adipocyte volume [2]. Plasma lipid-profile measurements showed that the total cholesterol levels were 30% lower in treated DIO mice relative to control DIO mice [2]/ 5-amino-1MQ reduced lipogenesis by 50% and 70%, respectively, compared to control untreated adipocytes [2].It is important to note that treatment of DIO mice with NNMT inhibitors did not impact food intake, but produced marked reductions in body weight, WAT mass, adipocyte size, and cholesterol levels with negligible toxicity or observable adverse effects [2]. In conclusion, current studies provides evidence for the use NNMT inhibitors as a therapeutic approach to manage diet-induced obesity and related metabolic comorbidities [2].
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