Absence of the xenobiotic acetylating enzymes NAT1 and NAT2 in mice leads to deregulation of energy metabolism associated with decreased ability to oxidize fatty acids

The NAT enzymes are polymorphic xenobiotic metabolizing enzymes that catalyze the transfer of an acetyl moiety from acetyl coenzyme A (acetyl-CoA) to the nitrogen or oxygen atom of primary arylamines, hydrazines, and their N-hydroxylated metabolites. NATs therefore play an important role in the detoxification and/or activation of arylamine drugs and carcinogens. The involvement of acetyl-CoA in energy metabolism suggests that there may be relationships between NAT activity and energy metabolism. Previous studies have suggested a role for NAT2 in insulin sensitivity that is exacerbated on high fat diet, using Nat1 knockout mice. To study mice with no NAT activity at all, we used a Nat1/Nat2 double-KO model, with animals fed either a regular chow or high fat/high sugar diet for 12 weeks. Analysis of basal parameters suggested a decrease in fatty-acid oxidation and hepatic gluconeogenesis. To further evaluate the cause of this, RNA was isolated and processed using Affymetrix Mouse Gene 2.0 microarrays. Adult male wildtype or Nat1/2 knockout mice were fed either a regular chow diet or high fat/high sucrose diet for 12 weeks (n = 16, divided into groups of 4 per condition). Similarly, adult female wildtype and Nat1/2 knockout mice (n = 3 each) were fed a high fat/high sucrose diet for 12 weeks.