Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

This landmark Nature paper from Barbara Kahn's group at Harvard established nicotinamide N-methyltransferase (NNMT) as a central regulator of energy metabolism and obesity. The authors observed that NNMT is strongly elevated in white adipose tissue and liver of obese mice and humans, and investigated whether this elevation was causally relevant.

Using antisense oligonucleotides (ASOs) to specifically knock down NNMT in adipose tissue and liver of high-fat diet–fed mice, the researchers demonstrated that treated animals became resistant to diet-induced obesity, with reduced body weight, lower adiposity, and improved insulin sensitivity — without any change in food intake.

Mechanistically, NNMT knockdown raised adipose levels of S-adenosylmethionine (SAM) and NAD+, activated NAD+-dependent SIRT1 signaling, upregulated genes linked to polyamine metabolism (ODC, SSAT) and lipid oxidation, and resulted in increased energy expenditure. NNMT was thus identified as a novel regulator of histone methylation, polyamine flux, and SIRT1 signaling.

This study was the cornerstone of the field: it validated NNMT as a therapeutic target for obesity and type 2 diabetes, and paved the way for the development of small-molecule inhibitors such as 5-Amino-1MQ that pharmacologically reproduce the genetic knockdown effect.