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Publication
Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin
resistance due to centrally mediated hypothyroidism.
Authors Brown WH, Gillum MP, Lee HY, Camporez JP, Zhang XM, Jeong JK, Alves TC, Erion
DM, Guigni BA, Kahn M, Samuel VT, Cravatt BF, Diano S, Shulman GI
Submitted By Submitted Externally on 11/10/2015
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2012
Date Published
Volume : Pages 109 : 14966 - 71
PubMed Reference 22912404
Abstract Fatty acid amide hydrolase (FAAH) knockout mice are prone to excess energy
storage and adiposity, whereas mutations in FAAH are associated with obesity in
humans. However, the molecular mechanism by which FAAH affects energy
expenditure (EE) remains unknown. Here we show that reduced energy expenditure
in FAAH(-/-) mice could be attributed to decreased circulating triiodothyronine
and thyroxine concentrations secondary to reduced mRNA expression of both
pituitary thyroid-stimulating hormone and hypothalamic thyrotropin-releasing
hormone. These reductions in the hypothalamic-pituitary-thyroid axis were
associated with activation of hypothalamic peroxisome proliferating-activated
receptor ? (PPAR?), and increased hypothalamic deiodinase 2 expression. Infusion
of NAEs (anandamide and palmitoylethanolamide) recapitulated increases in
PPAR?-mediated decreases in EE. FAAH(-/-) mice were also prone to diet-induced
hepatic insulin resistance, which could be attributed to increased hepatic
diacylglycerol content and protein kinase Ce activation. Our data indicate that
FAAH deletion, and the resulting increases in NAEs, predispose mice to ectopic
lipid storage and hepatic insulin resistance by promoting centrally mediated
hypothyroidism.




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