Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.
Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.
复制标题
重度抑郁症患者脑富集外泌体中的胰岛素受体底物：中枢胰岛素抵抗生物特征产生的途径。
DOI：
10.1038/s41380-020-0804-7
复制
发表时间：
2021-09
影响因子：
11
通讯作者：
Rasgon N
中科院分区：
文献类型：
--
作者：
Nasca C;Dobbin J;Bigio B;Watson K;de Angelis P;Kautz M;Cochran A;Mathé AA;Kocsis JH;Lee FS;Murrough JW;McEwen BS;Rasgon N
胰岛素信号传导对神经可塑性、脑代谢以及全身能量代谢至关重要。在啮齿类动物的研究中，脑胰岛素信号受损导致胰岛素抵抗（IR）调节突触可塑性和相应的行为功能。尽管发现了胰岛素的中枢作用，但大脑IR的体内分子机制直到最近才被证明很难在人脑中进行研究。在当前的研究中，我们利用了分子生物学的最新技术进步，并在此报告中发现，与年龄和性别匹配的健康对照组（HC）相比，重度抑郁症（MDD）受试者中富集L1CAM的外泌体数量增加。L1CAM是一种主要在大脑中表达的标志物。我们还报道了与年龄和性别匹配的HC相比，MDD患者L1CAM+外泌体中胰岛素受体底物-1 （IRS-1）的浓度增加。我们发现L1CAM+外泌体中IRS-1的表达与全身IR之间存在关系，这是通过HC中IR的稳态模型评估来评估的，但在MDD受试者中没有。L1CAM+外泌体中IRS-1水平的升高在重度抑郁症患者中更高，并且与自杀倾向和快感缺乏有关。最后，我们的数据表明MDD患者L1CAM+外泌体中IRS-1的丝氨酸-312磷酸化存在性别差异。这些发现为进一步开发有效治疗重度抑郁症的个性化医疗策略，创建脑IR的机制框架提供了一个起点。
Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in-vivo molecular mechanisms of brain IR until recently has proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared to age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared to age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.
登录
查看更多内容
DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
11
作者：
Lau, T.;Bigio, B.;Zelli, D.;McEwen, B. S.;Nasca, C.
通讯作者：
Nasca, C.
影响因子：
2.9
作者：
Grillo, C. A.;Tamashiro, K. L.;Reagan, L. P.
通讯作者：
Reagan, L. P.
影响因子：
5.3
作者：
Bonato, Jessica Mendes;Bassani, Taysa Bervian;Weffort de Oliveira, Rubia Maria
通讯作者：
Weffort de Oliveira, Rubia Maria
影响因子：
7.6
作者：
Cuccurazzu, Bruna;Bortolotto, Valeria;Grilli, Mariagrazia
通讯作者：
Grilli, Mariagrazia