Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction.
Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction.
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DOI：
10.1038/s41598-023-39643-z
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发表时间：
2023-08-04
影响因子：
4.6
通讯作者：
Coss, Djurdjica
中科院分区：
文献类型：
--
作者：
Ruggiero-Ruff, Rebecca E.;Villa, Pedro A.;Hijleh, Sarah Abu;Avalos, Bryant;DiPatrizio, Nicholas V.;Haga-Yamanaka, Sachiko;Coss, Djurdjica
脆性X信使核糖核蛋白1（FMR 1）基因的突变与脆性X综合征有关，脆性X综合征是智力残疾和自闭症最常见的单基因原因。受FMR 1突变影响的人肥胖发生率较高，但其机制在很大程度上尚不清楚。在目前的研究中，我们确定，与野生型对照组相比，雄性Fmr 1敲除小鼠（KO，Fmr 1 −/y），而不是雌性Fmr 1 −/−，表现出体重增加，类似于FMR 1突变的人类。各组之间的食物或水摄入量没有差异;然而，雄性Fmr 1-/y表现出较低的运动活动，尤其是在活跃期。此外，Fmr 1 −/y有嗅觉功能障碍，通过埋藏食物测试确定，虽然他们表现出强迫行为增加，通过大理石埋藏测试确定。由于嗅觉脑区与调节食物摄入的下丘脑区（包括也调节运动的POMC神经元）进行通信，因此我们检查了Fmr 1 −/y小鼠中POMC神经元的神经支配和数量。POMC神经元表达Fmrp，并且在Fmr 1 −/y中的POMC神经元具有更高的抑制性GABA能突触输入。与增加的抑制性神经支配一致，基于cFOS表达，Fmr 1 −/y小鼠中的POMC神经元表现出较低的活性。值得注意的是，与对照组相比，Fmr 1 −/y小鼠的POMC神经元更少，特别是在喙弓状核，这可能导致运动减少和体重增加。这些结果表明，在POMC神经元功能的调节和Fmr 1连锁肥胖的病因Fmr 1的作用。
Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In the current study, we determined that male Fmr1 knockout mice (KO, Fmr1−/y), but not female Fmr1−/−, exhibit increased weight when compared to wild-type controls, similarly to humans with FMR1 mutations. No differences in food or water intake were found between groups; however, male Fmr1−/y display lower locomotor activity, especially during their active phase. Moreover, Fmr1−/y have olfactory dysfunction determined by buried food test, although they exhibit increased compulsive behavior, determined by marble burying test. Since olfactory brain regions communicate with hypothalamic regions that regulate food intake, including POMC neurons that also regulate locomotion, we examined POMC neuron innervation and numbers in Fmr1−/y mice. POMC neurons express Fmrp, and POMC neurons in Fmr1−/y have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1−/y mice exhibit lower activity, based on cFOS expression. Notably, Fmr1−/y mice have fewer POMC neurons than controls, specifically in the rostral arcuate nucleus, which could contribute to decreased locomotion and increased body weight. These results suggest a role for Fmr1 in the regulation of POMC neuron function and the etiology of Fmr1-linked obesity.
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影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
4.9
作者：
Berman RF;Buijsen RA;Usdin K;Pintado E;Kooy F;Pretto D;Pessah IN;Nelson DL;Zalewski Z;Charlet-Bergeurand N;Willemsen R;Hukema RK
通讯作者：
Hukema RK
影响因子：
2.5
作者：
El Idrissi, A;Ding, XH;Dobkin, C
通讯作者：
Dobkin, C
影响因子：
2.5
作者：
Darnell, JC;Mostovetsky, O;Darnell, RB
通讯作者：
Darnell, RB
食物的感官检测快速调节弧形喂食电路。
影响因子：
64.5
作者：
Chen Y;Lin YC;Kuo TW;Knight ZA
通讯作者：
Knight ZA