A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice.
A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice.
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DOI：
10.7554/elife.81919
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发表时间：
2023-04-11
期刊：
影响因子：
7.7
通讯作者：
Hill MN
中科院分区：
文献类型：
--
作者：
Balsevich G;Petrie GN;Heinz DE;Singh A;Aukema RJ;Hunker AC;Vecchiarelli HA;Yau H;Sticht M;Thompson RJ;Lee FS;Zweifel LS;Chelikani PK;Gassen NC;Hill MN
脂肪酸酰胺水解酶（FAAH）降解内源性大麻素anandamide。FAAH的多态性（FAAH C385 A）降低FAAH表达，增加花生四烯酸水平，并增加肥胖的风险。然而，一些研究发现FAAH C385 A与肥胖之间没有关联。我们研究了环境背景是否控制FAAH C385 A对代谢结果的影响。使用C385 A基因敲入小鼠模型，我们发现FAAH A/A小鼠更容易受到糖皮质激素诱导的摄食过多，体重增加和下丘脑AMP激活蛋白激酶（AMPK）的激活。AMPK抑制阻断了FAAH A/A小鼠对糖皮质激素的放大的吞噬反应。FAAH敲低只在刺豚鼠相关蛋白（AgRP）神经元模仿夸张的喂养反应FAAH A/A小鼠糖皮质激素。FAAH A/A小鼠同样表现出对ghrelin的过度食欲反应，而在AgRP神经元中FAAH敲低使瘦素厌食反应减弱。总之，FAAH A/A基因型放大食欲反应和减少食欲反应，提供了一个假定的机制，解释了人类的不同发现。
Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (AgRP) neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings.
影响因子：
2.2
作者：
Schwarz NA;Rigby BR;La Bounty P;Shelmadine B;Bowden RG
通讯作者：
Bowden RG