<br>N-甲基-D-天冬氨酸受体的激活调节胰岛素敏感性和脂质代谢,Theranostics

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N-甲基-D-天冬氨酸受体的激活调节胰岛素敏感性和脂质代谢
Theranostics ( IF 12.4 ) Pub Date : 2021-1-1 , DOI: 10.7150/thno.51666
Xiao-Ting Huang ₁ , Jun-Xiao Yang ₂ , Zun Wang ₁ , Chen-Yu Zhang ₃ , Zi-Qiang Luo ₃ , Wei Liu ₁ , Si-Yuan Tang ₁

Affiliation

理由：尽管在了解脂肪变性和胰岛素抵抗机制方面已经取得了重大进展，但这些过程中调节因子的生理功能仍然很大程度上难以捉摸。有证据表明，谷氨酸/N-甲基-D-天冬氨酸受体（NMDAR）轴与急性肺损伤、肺动脉高压和糖尿病有关，但谷氨酸/NMDAR轴的具体代谢贡献尚不清楚。在这里，我们提供了动物、细胞和分子水平的数据，以支持谷氨酸/NMDAR 轴作为肥胖代谢综合征治疗靶点的作用。/n方法：我们检查了由高浓度诱导的肥胖小鼠中的谷氨酸水平。 -脂肪饮食（HFD）12周。为了评估 NMDAR 在胰岛素敏感性和脂质代谢中的作用，我们测试了美金刚（一种 NMDAR 拮抗剂）和 NMDA（一种 NMDAR 激动剂）对 HFD 或标准饲料喂养的小鼠的影响。分析了体外s NMDAR 在肝细胞中的作用，并研究了参与调节脂质代谢的潜在机制。/n 结果： HFD 处理的小鼠血清中谷氨酸含量增加。美金刚 (Memantine) 阻断 NMDAR 降低了肥胖小鼠对胰岛素抵抗和肝脂肪变性的易感性。 NMDA治疗6个月诱导小鼠肥胖，其特征是高血糖、高脂血症、胰岛素抵抗和肝脏病理改变。我们提供的体外证据表明，NMDAR 激活通过促进脂质积累而促进肥胖代谢综合征。 NMDAR 抑制减弱了棕榈酸诱导的脂质积累。从机制上讲，NMDAR 激活通过降低 PPARα 磷酸化和活性来损害脂肪酸氧化。 NMDAR 激活诱导的 PPARα 活性降低是由 ERK1/2 信号可逆介导的。/n结论：这些发现表明，靶向 NMDAR 可能是肥胖代谢综合征的一种有前景的治疗策略。

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Activation of N-methyl-D-aspartate receptor regulates insulin sensitivity and lipid metabolism

Rationale: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity./nMethods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitros NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated./nResults: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling./nConclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity.

更新日期：2021-01-01

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