Peripheral effects of FAAH deficiency on fuel and energy homeostasis: role of dysregulated lysine acetylation

• Published in: PloS one 2012-03, Vol.7 (3), p.e33717-e33717
• Main Authors: Vaitheesvaran, Bhavapriya, Yang, Li, Hartil, Kirsten, Glaser, Sherrye, Yazulla, Stephen, Bruce, James E, Kurland, Irwin J
• Format: Article
• Language: English
• Subjects: Acetates; Acetyl Coenzyme A - genetics; Acetyl Coenzyme A - metabolism; Acetylation; Alcohol dehydrogenase; Alcoholic beverages; Aldolase; Amidohydrolases - genetics; Amidohydrolases - metabolism; Analysis; Animal models; Animals; Aspartate; Biology; Body composition; Body weight; Calorimetry; Cannabinoids; Chemistry; Cholesterol; Chromatography; Citric acid; Dehydrogenase; Diabetes; Diabetes mellitus; Dihydroxyacetone; Energy; Energy balance; Energy Metabolism; Enzymes; Fatty acids; Fatty-acid amide hydrolase; Gene expression; Gene Expression Regulation, Enzymologic; Gene mutation; Genetic aspects; Glucose; Glucose - genetics; Glucose - metabolism; Glycerol; Glycogen; Homeostasis; Humans; Hydrolase; Hydrolases; Hydrolysis; Insulin; Insulin resistance; Ligands; Lipid Metabolism; Lipids; Liver; Liver cirrhosis; Liver diseases; Lysine; Lysine - genetics; Lysine - metabolism; Malate; Mass spectrometry; Medicine; Metabolism; Metabolites; Mice; Mice, Knockout; Muscles; Musculoskeletal system; Mutation; Neurobiology; Neurosciences; Obesity; Obesity - enzymology; Obesity - genetics; Oxygen; Oxygen consumption; Phenotyping; Physiological aspects; Plasma; Prediabetic state; Rodents; Scientific imaging; Skeletal muscle; Stable isotopes; Triglycerides
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033717

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. 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