Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice

This study conducted at the University of Texas Medical Branch characterized 5-Amino-1MQ (5-amino-1-methylquinolinium) as the first selective, membrane-permeable inhibitor of nicotinamide N-methyltransferase (NNMT) capable of reversing diet-induced obesity. NNMT is an enzyme highly expressed in white adipose tissue that consumes NAD+ and S-adenosylmethionine (SAM) to methylate nicotinamide, a process linked to fat accumulation and insulin resistance.

The authors screened quinolinium derivatives and identified 5-Amino-1MQ as the most potent candidate, with excellent passive and active permeability in PAMPA and Caco-2 assays. In vitro, the compound reduced NNMT activity in 3T3-L1 adipocytes, shrank fat cell size, raised intracellular NAD+ and SAM levels, and suppressed lipogenesis — without inhibiting other SAM-dependent methyltransferases or NAD+ salvage pathway enzymes.

In vivo, diet-induced obese mice received 5-Amino-1MQ intraperitoneally for 11 days. Treatment significantly reduced body weight, white adipose tissue mass, adipocyte size, and total plasma cholesterol, without affecting food intake, lean mass, or general health markers — suggesting the effect is driven by metabolic reprogramming rather than appetite suppression.

This work was seminal in validating NNMT as a viable pharmacological target for obesity and metabolic syndrome, and in establishing 5-Amino-1MQ as the reference tool compound in NNMT research. It provided the mechanistic basis for all subsequent interest in NNMT inhibitors as a strategy for fat loss without compromising satiety or muscle mass.