Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp -/- mice.
The tissue-specific sources and regulated production of physiological signals that modulate food intake are incompletely understood. Previous work showed that L-Fabp(-/-) mice are protected against obesity and hepatic steatosis induced by a high-fat diet, findings at odds with an apparent obesity phenotype in a distinct line of aged L-Fabp(-/-) mice. Here we show that the lean phenotype in L-Fabp(-/-) mice is recapitulated in aged, chow-fed mice and correlates with alterations in hepatic, but not intestinal, fatty acid amide metabolism. L-Fabp(-/-) mice exhibited short-term changes in feeding behavior with decreased food intake, which was associated with reduced abundance of key signaling fatty acid ethanolamides, including oleoylethanolamide (OEA, an agonist of PPARα) and anandamide (AEA, an agonist of cannabinoid receptors), in the liver. These reductions were associated with increased expression and activity of hepatic fatty acid amide hydrolase-1, the enzyme that degrades both OEA and AEA. Moreover, L-Fabp(-/-) mice demonstrated attenuated responses to OEA administration, which was completely reversed with an enhanced response after administration of a nonhydrolyzable OEA analog. These findings demonstrate a role for L-Fabp in attenuating obesity and hepatic steatosis, and they suggest that hepatic fatty acid amide metabolism is altered in L-Fabp(-/-) mice.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Elizabeth P
EP
Newberry
Susan M
SM
Kennedy
Yan
Y
Xie
Jianyang
J
Luo
Rosanne M
RM
Crooke
Mark J
MJ
Graham
Jin
J
Fu
Daniele
D
Piomelli
Nicholas O
NO
Davidson
D050154:Adiposity; D000367:Age Factors; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D001835:Body Weight; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D018752:Diet, Fat-Restricted; D063388:Endocannabinoids; D004789:Enzyme Activation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology*; D005247:Feeding Behavior; D005260:Female; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D009829:Oleic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000494:pharmacology; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D050556:Fatty Acid-Binding Proteins; D009829:Oleic Acids; D047495:PPAR gamma; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C493320:Fabp1 protein, mouse; C488250:oleoylethanolamide; C078814:anandamide