Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism
Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism
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DOI：
10.1073/pnas.1212887109
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发表时间：
2012-09-11
影响因子：
11.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Brown, Whitney H.;Gillum, Matthew P.;Shulman, Gerald I.
脂肪酸酰胺水解酶（FAAH）基因敲除小鼠容易出现能量储存过多和肥胖，而FAAH基因突变与人类肥胖相关。然而，FAAH影响能量消耗（EE）的分子机制仍然未知。在这里，我们表明，减少FAAH（-/-）小鼠的能量消耗可能是由于降低循环三碘甲状腺原氨酸和甲状腺素浓度继发于垂体促甲状腺激素和下丘脑促甲状腺激素释放激素的mRNA表达减少。下丘脑-垂体-甲状腺轴的这些减少与下丘脑过氧化物酶体增殖激活受体γ（PPAR γ）的激活和下丘脑脱碘酶2表达的增加有关。NAE（anandamide和palmitoyethanolamide）的输注重现了PPAR的增加。FAAH（-/-）小鼠也容易发生饮食诱导的肝脏胰岛素抵抗，这可能归因于肝脏二酰甘油含量增加和蛋白激酶C β激活。我们的数据表明，FAAH缺失，以及由此产生的NAE增加，通过促进中枢介导的甲状腺功能减退，使小鼠易发生异位脂质储存和肝脏胰岛素抵抗。
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 gamma (PPAR gamma), 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 C epsilon 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.