Peripheral Effects of FAAH Deficiency on Fuel and Energy Homeostasis: Role of Dysregulated Lysine Acetylation

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<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.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

The influence of dietary nucleotides on erythrocyte membrane fatty acids and plasma lipids in preterm infants

OBJECTIVE: The objective of this study was to evaluate whether a regular formula for premature infants supplemented with nucleotides has any influence on plasma lipids and erythrocyte membrane fatty acids. METHODS: Preterm infants fed either human milk supplemented with human milk protein (HM, n = 14), nucleotide-supplemented preterm formula (NF, n = 13), or a regular preterm formula (F, n = 13) were included in the study. The NF was supplemented with 18.2 mg cytidine monophosphate/l (CMP), 7.0 mg uridine monophosphate/l (UMP), 6.4 mg adenosine monophosphate/l (AMP), 3.0 mg inosine monophosphate/l (IMP) and 3.0 mg guanosine monophosphate/l (GMP). RESULTS: There were significantly higher concentrations of triglycerides (TG) in infants fed NF compared to those fed F (191.42 +/- 79.58 vs 108.21 +/- 43.73, p < 0.001, mean +/- SD lipid concentrations, mg/100 ml plasma). Infants fed F had significantly lower concentrations of total cholesterol (94.34 +/- 11.71 vs 115.69 +/- 39.29, p < 0.01) and TG in plasma (108.21 +/- 43.73 vs 172.27 +/- 68.19, p < 0.001, mean +/- SD lipid concentrations, mg/100 ml plasma) when compared to HM-fed infants. There were no significant differences in any of the erythrocyte membrane fatty acids and total long-chain polyunsaturated fatty acids (LC-PUFA) between NF and F during the study period (6 weeks). Furthermore, total LC-PUFA and docosahexaenoic acid (DHA) concentrations in red blood cell were not significantly different when infants fed NF were compared to those fed HM. In contrast, however, infants fed F had significantly lower concentrations of total n-3 LC-PUFA (p < 0.01) and DHA (p < 0.01) than those found in HM-fed infants. CONCLUSIONS: These results do not suggest an effect of nucleotides on the red blood cell LC-PUFA profile in preterm infants. However, the nucleotides may increase the concentrations of triglycerides in plasma