Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro assays and mouse model with no human data
PubMed 29155147 · doi:10.1016/j.bcp.2017.11.007
What was done
The authors investigated the pharmacological, mechanistic, and metabolic properties of small-molecule nicotinamide N-methyltransferase (NNMT) inhibitors based on methylquinolinium scaffolds. Membrane permeability was tested using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was evaluated against SAM-dependent methyltransferases and NAD+ salvage pathway enzymes. Intracellular metabolites (1-MNA, NAD+, SAM) and lipogenesis were measured in cultured adipocytes. A potent NNMT inhibitor was administered systemically to diet-induced obese mice fed a high-fat diet to evaluate effects on body weight, white adipose mass, adipocyte size, plasma total cholesterol, and food intake.
What was found
No specific numerical values or effect sizes are reported in the abstract. Methylquinolinium analogues showed membrane permeability and high selectivity without inhibiting related SAM-dependent methyltransferases or NAD+ salvage pathway enzymes. In adipocytes, NNMT inhibition reduced 1-MNA, increased NAD+ and SAM, and suppressed lipogenesis. In diet-induced obese mice, systemic inhibitor treatment significantly reduced body weight, white adipose mass, adipocyte size, and plasma total cholesterol without altering food intake or producing observed adverse effects.
Why it matters
This study provides preclinical validation for NNMT inhibition as a targeted mechanism to reverse obesity and improve metabolic profiles without reducing caloric intake.
Limits
The abstract provides no sample sizes (n is unstated), no numerical data, and no confidence intervals. Findings are limited to cell culture and a rodent model, meaning clinical efficacy, pharmacokinetics, and human safety are unmeasured.
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