A new study in mice shows that the enzyme nicotinamide N-methyltransferase (Nnmt) is a key mediator of obesity and its metabolic complications (Nature 508, 258–262, 2014).
Nnmt expression and activity is known to be upregulated in the fat tissue of obese humans and rodents. Barbara Kahn and her colleagues now find that knockdown of Nnmt expression in adipose tissue in mice increased their energy expenditure, protecting them from diet-induced obesity and insulin insensitivity.
They also dissect the metabolic pathways altered by the lack of Nnmt to explain the increase in energy expenditure in these animals. The absence of this enzyme results in increased cellular amounts of its substrate nicotinamide (Nam) as well as S-adenosylmethionine (SAM), which Nnmt uses as a methyl donor to metabolize Nam. This boost in Nam levels led to activation of sirtuins, which are known to increase energy expenditure, and SAM was shown to feed into the polyamine flux pathway, which results in the same metabolic effect.
These findings provide a metabolic explanation of how upregulation of Nnmt may contribute to development of disease in obese individuals and suggest that this enzyme may be a potent target to treat obesity.
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Levinson, R. An energizing flux. Nat Med 20, 483 (2014). https://doi.org/10.1038/nm.3575