BACKGROUND: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, 
hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene 
mutations are associated with increased body weight and obesity. In our present 
study, using targeted metabolite and lipid profiling, and new global acetylome 
profiling methodologies, we examined the role of the liver on fuel and energy 
homeostasis in whole body FAAH(-/-) mice.
METHODOLOGY/PRINCIPAL FINDINGS: FAAH(-/-) mice exhibit altered energy 
homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). 
FAAH(-/-) mice are hyperinsulinemic and have adipose, skeletal and hepatic 
insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed 
state skeletal muscle and liver triglyceride levels was increased 2-3 fold, 
while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol 
synthesis was decreased 22% in FAAH(-/-) mice. Dysregulated hepatic FAAH(-/-) 
lysine acetylation was consistent with their metabolite profiling. Fasted to fed 
increases in hepatic FAAH(-/-) acetyl-CoA (85%, p<0.01) corresponded to similar 
increases in citrate levels (45%). Altered FAAH(-/-) mitochondrial malate 
dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, 
was consistent with our observation of a 25% decrease in fed malate and 
aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and 
glycerol-3-P levels in FAAH(-/-) mice was consistent with a compensating 
contribution from decreased acetylation of fed FAAH(-/-) aldolase B. Fed 
FAAH(-/-) alcohol dehydrogenase (ADH) acetylation was also decreased.
CONCLUSIONS/SIGNIFICANCE: Whole body FAAH deletion contributes to a pre-diabetic 
phenotype by mechanisms resulting in impairment of hepatic glucose and lipid 
metabolism. FAAH(-/-) mice had altered hepatic lysine acetylation, the pattern 
sharing similarities with acetylation changes reported with chronic alcohol 
treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA 
hydrolysis could support the liver's role in fostering the pre-diabetic state, 
and may reflect part of the mechanism underlying the hepatic effects of 
endocannabinoids in alcoholic liver disease mouse models.