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Unlike pharmaceuticals, which must be tested and approved before they go to market and then comply with strict regulations about how they can be marketed, the US Food and Drug Administration doesnt have the authority to approve dietary supplements before they are marketed

This was established as an important research question to be funded as part of the James Lind Alliance priority-setting partnership with the Pernicious Anaemia Society

Thus, there is a critical need for more effective pharmacological interventions that improve long-term management of obesity and its comorbidities.[11] Recently, nicotinamide-N-methyltransferase (NNMT) has emerged as a novel mechanism-of-action target in the adipose tissue to treat obesity and associated T2D.[1215] 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.[16] Furthermore, 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.[13, 14] Importantly, mice fed a high-fat diet and treated with antisense oligonucleotides (ASOs) that reduced adipose NNMT expression were protected from diet-induced obesity (DIO) and showed reduced adiposity compared to control animals.[12] Using structure-guided design and binding calculations, we recently generated potent small molecule NNMT inhibitors around a methylquinolinium (MQ)-scaffold.[17] In the present study, we extend these findings to show that the small molecule NNMT inhibitors are highly membrane-permeable, selective inhibitors, which reduce intracellular 1-MNA levels and prevent lipogenesis in vitro