From population to neuron: exploring common mediators for metabolic problems and mental illnesses.
From population to neuron: exploring common mediators for metabolic problems and mental illnesses.
复制标题
DOI：
10.1038/s41380-020-00939-5
复制
发表时间：
2021-08
影响因子：
11
通讯作者：
Sawa A
中科院分区：
文献类型：
--
作者：
Takayanagi Y;Ishizuka K;Laursen TM;Yukitake H;Yang K;Cascella NG;Ueda S;Sumitomo A;Narita Z;Horiuchi Y;Niwa M;Taguchi A;White MF;Eaton WW;Mortensen PB;Sakurai T;Sawa A
精神分裂症(SZ)和双相情感障碍(BP)等重大精神疾病经常伴随着代谢疾病，但它们之间的关系仍然不清楚，特别是在机制水平上。我们实施了从种群到神经元的方法，将基于种群的流行病学分析与基于流行病学研究的假设建立的细胞和动物模型的神经生物学实验相结合。我们描述了高质量的人群数据，来自SZ或BP患者的嗅神经细胞活检，健康受试者，以及为胰岛素信号而进行基因改造的小鼠。我们访问了丹麦登记处，观察到(1)在SZ或BP患者中糖尿病的发病率更高，(2)在同一大队列中，糖尿病患者的主要精神疾病的发病率更高。这些流行病学数据表明，糖尿病和主要精神疾病中都存在常见的病理生理介质。我们假设与胰岛素抵抗相关的分子可能是这种常见的媒介，然后通过使用从患者和健康对照身上活检的两组独立的嗅神经细胞来验证这一假设。在第一组中，我们证实了在SZ患者和对照组之间存在显著差异的基因中的胰岛素信号相关分子的丰富，这些基因在无偏见的表达谱数据中存在显著差异。在第二组中，来自非糖尿病前期或糖尿病患者的SZ和BP患者的嗅神经细胞在胰岛素刺激下显示IRS2酪氨酸磷酸化降低，这表明存在胰岛素抵抗。这些细胞还表现出IRS1蛋白在丝氨酸-312位的磷酸化上调(无胰岛素刺激)，进一步支持了SZ患者嗅神经细胞存在胰岛素抵抗的概念。最后，Irs2基因敲除小鼠对苯丙胺表现出异常反应，这在一些患有严重精神疾病的患者中也可以观察到。主要精神疾病和糖尿病之间的双向关系表明，在这些精神和身体状况下，可能存在与胰岛素抵抗相关的常见病理生理介质。
Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of “from population to neuron”, combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.
登录
查看更多内容
DOI：
10.1176/appi.ajp.2015.14091200
发表时间：
2016-04-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Clementz BA;Sweeney JA;Hamm JP;Ivleva EI;Ethridge LE;Pearlson GD;Keshavan MS;Tamminga CA
通讯作者：
Tamminga CA
影响因子：
11
作者：
Landek-Salgado MA;Faust TE;Sawa A
通讯作者：
Sawa A
影响因子：
17.1
作者：
Axelsson, Annika S.;Tubbs, Emily;Rosengren, Anders H.
通讯作者：
Rosengren, Anders H.
影响因子：
168.9
作者：
Kahn, Steven E.;Cooper, Mark E.;Del Prato, Stefano
通讯作者：
Del Prato, Stefano
影响因子：
13.5
作者：
Banks, William A.;Owen, Joshua B.;Erickson, Michelle A.
通讯作者：
Erickson, Michelle A.