Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity.
Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity.
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DOI：
10.1016/j.molmet.2023.101744
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发表时间：
2023-07
影响因子：
8.1
通讯作者：
Rahimi, Nader
中科院分区：
文献类型：
--
作者：
Lotfollahzadeh, Saran;Xia, Chaoshuang;Amraei, Razie;Hua, Ning;Kandror, Konstantin V.;Farmer, Stephen R.;Wei, Wenyi;Costello, Catherine E.;Chitalia, Vipul;Rahimi, Nader
肥胖是一种复杂的疾病，与2型糖尿病等慢性疾病有关。主要内在障碍性NOTCH 2相关受体2（MINAR 2）是一种研究不足的蛋白质，在肥胖和代谢中的作用未知。本研究的目的是确定Minar 2对脂肪组织和肥胖的影响。我们产生Minar 2敲除（KO）小鼠，并使用各种分子，蛋白质组学，生物化学，组织病理学和细胞培养研究，以确定Minar 2在脂肪细胞中的病理生理作用。我们证明了Minar 2的失活导致了具有肥大脂肪细胞的体脂增加。高脂肪饮食的Minar 2 KO小鼠发展肥胖和葡萄糖耐量和代谢受损。在机制上，Minar 2与哺乳动物TOR复合物1（mTORC 1）的特异性和必需组分Raptor相互作用并抑制mTOR活化。mTOR在Minar 2缺陷的脂肪细胞中过度活化，HEK-293细胞中Minar 2的过度表达抑制mTOR活化和mTORC 1底物（包括S6激酶和4 E-BP 1）的磷酸化。我们的研究结果确定Minar 2是mTORC 1的一种新的生理负调节因子，在肥胖和代谢紊乱中起关键作用。MINAR 2的表达或激活受损可能导致肥胖和肥胖相关疾病。小鼠中Minar 2的失活使小鼠易患饮食诱导的肥胖症。高脂饮食的Minar 2 KO小鼠发展为肥胖并显示葡萄糖代谢受损。Minar 2与Raptor相互作用并调节mTORC 1信号传导。
Obesity is a complex disorder and is linked to chronic diseases such as type 2 diabetes. Major intrinsically disordered NOTCH2-associated receptor2 (MINAR2) is an understudied protein with an unknown role in obesity and metabolism. The purpose of this study was to determine the impact of Minar2 on adipose tissues and obesity. We generated Minar2 knockout (KO) mice and used various molecular, proteomic, biochemical, histopathology, and cell culture studies to determine the pathophysiological role of Minar2 in adipocytes. We demonstrated that the inactivation of Minar2 results in increased body fat with hypertrophic adipocytes. Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism. Mechanistically, Minar2 interacts with Raptor, a specific and essential component of mammalian TOR complex 1 (mTORC1) and inhibits mTOR activation. mTOR is hyperactivated in the adipocytes deficient for Minar2 and over-expression of Minar2 in HEK-293 cells inhibited mTOR activation and phosphorylation of mTORC1 substrates, including S6 kinase, and 4E-BP1. Our findings identified Minar2 as a novel physiological negative regulator of mTORC1 with a key role in obesity and metabolic disorders. Impaired expression or activation of MINAR2 could lead to obesity and obesity-associated diseases. Inactivation of Minar2 in mice predisposes mice to diet-induced obesity. Minar2 KO mice on high-fat diet develop obesity and display impaired glucose metabolism. Minar2 interacts with Raptor and regulates mTORC1 signaling.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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