Hepatic Deletion of Nicotinamide N-Methyltransferase Prevents Body Weight Gain and Improves Insulin Sensitivity in Mice on Standard Diet

Aims Nicotinamide N-methyltransferase (NNMT) is linked to obesity and related metabolic disease with its highest expression in human liver and murine adipose tissue (AT). We recently published genetically deficient Nnmt knockout (KO) mice reporting sex- and diet-specific differences in their metabolic phenotype. Therefore, we generated conditional Nnmt KO mice to dissect its metabolic role.

Methods We extensively characterized conditional AT-specific (ANNMT- / -) and liver-specific Nnmt-deficient (LNNMT- / -) KO mice feeding either standard (STD), high-fat (HFD) or Western diet (WD) and investigated metabolic parameters, weight gain, body composition, energy balance, glucose homeostasis and insulin sensitivity.

Results ANNMT- / - mice showed no obvious metabolic discrepancy to wildtype control (WT) on any diet including comparable weight gain, body composition, glucose tolerance and insulin sensitivity although we found a strong reduction of Nnmt and 1-methylnicotinamide (MNAM) concentration in AT without affecting liver. Whereas, LNNMT- / - mice showed almost no Nnmt expression and reduced MNAM in liver while plasma and AT MNAM was unchanged. Weight and fat gain were prevented in LNNMT- / - mice during STD and WD along with decreased plasma insulin and lower liver weights. However, hepatic Nnmt deletion did not affect glucose homeostasis regardless of diet. In hyperinsulinemic-euglycemic clamps, we observed elevated glucose infusion rates and improved glucose uptake in LNNMT- / - albeit only on STD but not on HFD.

Conclusion ANNMT- / - revealed no prominent metabolic feature whereas LNNMT- / - showed improved body composition with decreased body weight and fat under STD and WD. However, LNNMT- / - had no benefit on glucose handling while insulin sensitivity was enhanced during STD.

Interessenskonflikt

Sebastian Brachs and Joachim Spranger received research support in relation to the joint laboratory between Charité–Universitätsmedizin Berlin and Sanofi.

Ralf Elvert, Felix Bärenz,Sven Ruf, Mostafa Kabiri & Aimo Kannt were employees of Sanofi during this project.

Maria Brachs is an employee of Treamid Therapeutics GmbH and Myelo Therapeutics GmbH. No other potential conflicts of interest relevant to this article were reported.

Publication History

Article published online:
06 May 2021