For those who do suffer this condition, investigators from Beth Israel Deaconess Medical Center (BIDMC) say they have found a genetic “switch” that can accelerate a person’s basal metabolic rate – leading to a dramatic reduction in the risk for obesity and diabetes.
Their research, published in the journal Nature, involves turning off a gene that encodes a protein called nicotinamide N-methyltransferase (NNMT), which is found in the fat cells and the liver. NNMT is known to process vitamin B3 and has been previously linked with certain types of cancers.
In order to lower the expression of the NNMT gene, the researchers used antisense oligonucleotide (ASO) technology, which allowed them to interfere with the expression of the gene only in the fat cells and the liver. ASOs are short molecular strings of DNA, which can be designed to prevent the synthesis of specific proteins.
When the researchers turned off the NNMT gene in mice on high-fat diets, the mice did not gain as much weight compared to when the NNMT gene was functioning normally. Furthermore, the mice did not change their eating or exercise habits, meaning the NNMT solely affected the mice’s basal metabolic rates.
More than 1/3 of adults in the United States are considered obese, and 25.8 million people – 8.3 percent of the American population – have diabetes, according to the Centers for Disease Control and Prevention.
Nature – Metabolism: Targeting a fat-accumulation gene An enzyme that links two metabolic hubs has been found to be upregulated in the fat cells of overweight mice. Inhibition of the gene encoding this enzyme protects mice from diet-induced obesity.
In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. 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. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism5. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation6. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine–spermine N1-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism7, 8. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD+-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.
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