Implication of neuronal calcium sensor protein 1 (NCS-1) in metabolic stress and obesity

神经元钙传感器蛋白 1 (NCS-1) 在代谢应激和肥胖中的意义

• 批准号: 269219700
• 负责人: Professor Dr. Olaf Pongs
• 金额: --
• 依托单位: Fachrichtung Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269219700?language=en
• 关键词: Implication; neuronal; calcium; sensor; protein

Obesity, a spreading worldwide health problem, represents a major risk factor for the development of type 2 diabetes. Increased levels of saturated free fatty acid in the blood causes metabolic stress and insulin resistance. The mixed lineage protein kinase (MLK) pathway plays a critical role for diet-induced insulin resistance and obesity. An understanding of the mechanisms that regulate the activity of this pathway is therefore important for the development of therapeutic interventions in the treatment of obesity-related metabolic stress. This proposal focuses on the activity of neuronal calcium sensor protein-1 (NCS-1) in adipose tissue of the mouse and the role of NCS-1 in the metabolic stress response to obesity. It involves the mixed-lineage kinase (MLK) pathway that activates c-Jun NH2-terminal kinase (JNK). Using NCS-1 knock-out (NCS-1-/-) mice, which possess an elevated JNK activity, and a combination of NCS-1-/- with MLK2/MLK3 deficient (Map3k10-/- Map3k11-/- compound) mice, the proposal has three major objectives: i) unravel the physiological role of NCS-1 in relation to the obese phenotype of NCS-1-/- mice; ii) further characterize the type 2 diabetes phenotype of NCS-1-/- mice, which is associated with alterations in the metabolic stress response observed under a high-fat diet; iii) explore the role of NCS-1 in the mixed-lineage protein kinase pathway leading to increased JNK activity in NCS-1-/- mice. We expect that the results of our studies contribute to a better understanding of the regulation of the metabolic stress response to obesity.

肥胖症是一种蔓延的全球健康问题，是2型糖尿病发展的主要危险因素。血液中饱和游离脂肪酸的水平增加会导致代谢应激和胰岛素抵抗。混合谱系蛋白激酶（MLK）途径在饮食诱导的胰岛素抵抗和肥胖症中起着至关重要的作用。因此，对调节该途径活性的机制的理解对于在治疗与肥胖相关的代谢应激治疗中的治疗干预措施的发展至关重要。该建议的重点是神经元钙传感器蛋白-1（NCS-1）在小鼠的脂肪组织中的活性以及NCS-1在代谢应激对肥胖症反应中的作用。它涉及激活C-Jun NH2-末端激酶（JNK）的混合细胞激酶（MLK）途径。使用具有升高JNK活性的NCS-1敲除（NCS-1 - / - ）小鼠，并将NCS-1 - / - 与MLK2/MLK3缺陷（MAP3K10 - / - MAP3K11 - / - 化合物）组合组合，该建议具有三个主要目的：I）ncs-nc-s-1的生理作用 - 与ncs-1的生理作用相关 - ii）进一步表征了NCS-1 - / - 小鼠的2型糖尿病表型，这与在高脂饮食下观察到的代谢应激反应的改变有关； iii）探讨NCS-1在混合元素激酶途径中的作用，从而导致NCS-1 - / - 小鼠的JNK活性增加。我们期望我们的研究结果有助于更好地理解对肥胖症的代谢压力反应的调节。