DEsire - DEP-1 as potential modulator of cerebral insulin resistance and emotional behavior

DEsire - DEP-1 作为脑胰岛素抵抗和情绪行为的潜在调节剂

• 批准号: 445157429
• 负责人: Professor Dr. Kai Kappert
• 金额: --
• 依托单位: Center for Cardiovascular Research (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445157429?language=en
• 关键词: DEsire; DEP; potential; modulator; cerebral

More than 650 million people worldwide are overweight and 400 million suffer from diabetes. Insulin resistance, a condition described by an inadequate response to insulin, characterizes obesity and diabetes. Importantly, insulin resistance, often triggered by diet-induced obesity, not only manifests in peripheral tissues but also in the brain. Therefore, diabetes and insulin resistance are associated with altered brain function, cognition impairment and mood disorders. A serious category of mood change involves depression. Obese patients are at an increased risk of depression. Vice versa, depressed patients develop diabetes more often. The insulin and IGF-1 receptor (IR, IGF-1R), both receptor tyrosine kinases, play a relevant role in modulating neuronal functions. These receptors are expressed throughout the brain in areas affecting metabolism, cognition and mood. We could show that in mice an IR deficiency in the brain results in depressive-like behavior and anxiety.Tyrosine phosphorylation and thus the function of both receptors is negatively regulated by protein tyrosine phosphatases (PTPs). Increased expression of PTPs is present in both mice with insulin resistance and in mice characterized by depressive-like behavior. We were able to show that the reduction of the PTP density-enhanced phosphatase-1 (DEP-1) protects against diet-induced insulin resistance. Unpublished own data show that decreased expression of DEP-1 in neuronal cells enhances insulin-mediated tyrosine phosphorylation of the IR and IGF-1R. In addition, brains of obese, insulin-resistant mice show increased expression of DEP-1. Also, diabetic patients are characterized by increased DEP-1 gene expression and genetic variations of the DEP-1 gene locus associate with altered sleep patterns and nightmares. Therefore, we hypothesize that DEP-1 is a hitherto unidentified modulator of cerebral insulin resistance that affects both metabolism and emotional behavior.DEP-1 will be postnatally deleted in brain structures implicated in insulin and dopamine signaling in order to investigate the function of DEP-1 on metabolism and emotional behavior over time in lean and high fat diet-fed mice. For this, CamKIIα Cre mice are bred with DEP-1lox/lox mice. Moreover, using N2a dopaminergic neurons, we characterize the interaction of IR and IGF-1R with DEP-1, including the impact of DEP-1 on synaptic plasticity. Applying a proximity ligation assay the spatial brain distribution of IR/IGF-1R, DEP-1 and their interaction in vivo will be assessed. Finally, we analyze the metabolic regulation of PTP activity in different brain areas of the dopaminergic system by tyrosine dephosphorylation assays.The overall goal is in the characterization of DEP-1 as hitherto unrecognized potential modulator of cerebral insulin resistance and emotional behavior.

全世界有超过6.5亿人超重，4亿人患有糖尿病。胰岛素抵抗是一种对胰岛素反应不足的疾病，是肥胖和糖尿病的特征。重要的是，胰岛素抵抗，通常由饮食诱导的肥胖引发，不仅表现在外周组织，而且在大脑中。因此，糖尿病和胰岛素抵抗与脑功能改变、认知障碍和情绪障碍有关。情绪变化的一个严重类别涉及抑郁症。肥胖患者患抑郁症的风险增加。反之亦然，抑郁症患者更容易患糖尿病。胰岛素和IGF-1受体（IR，IGF-1 R），这两种受体酪氨酸激酶，在调节神经元功能中发挥相关作用。这些受体在整个大脑中影响新陈代谢、认知和情绪的区域中表达。我们可以证明，在小鼠中，脑中IR缺乏导致抑郁样行为和焦虑。酪氨酸磷酸化，从而两种受体的功能受到蛋白酪氨酸磷酸酶（PTPs）的负调控。PTPs的表达增加存在于具有胰岛素抵抗的小鼠和以抑郁样行为为特征的小鼠中。我们能够证明PTP密度增强磷酸酶-1（DEP-1）的减少可以防止饮食诱导的胰岛素抵抗。未发表的数据显示，神经元细胞中DEP-1表达的降低增强了胰岛素介导的IR和IGF-1 R的酪氨酸磷酸化。此外，肥胖的胰岛素抵抗小鼠的大脑显示DEP-1的表达增加。此外，糖尿病患者的特征在于增加的DEP-1基因表达和DEP-1基因座的遗传变异与改变的睡眠模式和噩梦相关。因此，我们假设DEP-1是一个迄今尚未确定的脑胰岛素抵抗的调节剂，影响代谢和情绪行为，DEP-1将在出生后删除的脑结构中涉及胰岛素和多巴胺信号转导，以研究DEP-1的功能，随着时间的推移，在瘦和高脂肪饮食喂养的小鼠的代谢和情绪行为。为此，CamKIIα Cre小鼠与DEP-1 lox/lox小鼠交配。此外，使用N2 a多巴胺能神经元，我们表征IR和IGF-1 R与DEP-1的相互作用，包括DEP-1对突触可塑性的影响。应用邻近连接测定法，将评估IR/IGF-1 R、DEP-1的空间脑分布及其在体内的相互作用。最后，我们通过酪氨酸去磷酸化分析来分析PTP活性在多巴胺能系统不同脑区的代谢调节，总体目标是将DEP-1表征为迄今为止未被认识到的脑胰岛素抵抗和情绪行为的潜在调节剂。