Abstract
BackgroundFAAH (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 FindingsFAAH−/− 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/SignificanceWhole 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.
Highlights
Obesity, recognized as a chronic disease, is the second leading cause of preventable death
Increased body weight could be attributed, in part, to increased food intake by FAAH2/2 mice, which consumed 26% more food/day compared to wild-types
In our present study we have examined the metabolic effect of FAA hydrolase (FAAH) gene deletion on fuel switching and energy homeostasis
Summary
Recognized as a chronic disease, is the second leading cause of preventable death. In 2008 the World Health Organization estimated 1.5 billion adults, 20 and older, were overweight. Of these over 200 million men and nearly 300 million women were obese (http://www.who.int/mediacentre/factsheets/ fs311/en/) [1]. Several studies have shown that the endocannabinoid system is dysregulated [7,8,9,10] and activated in peripheral tissues [11,12,13] during obesity. 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 FAAH2/2 mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
