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

肥胖是一个全球性的健康问题，是2型糖尿病的主要危险因素。血液中饱和游离脂肪酸水平的增加会导致代谢压力和胰岛素抵抗。混合谱系蛋白激酶（MLK）通路在饮食诱导的胰岛素抵抗和肥胖中起关键作用。因此，了解调节这一途径活性的机制对于开发治疗肥胖相关代谢应激的干预措施非常重要。本研究主要关注小鼠脂肪组织中神经元钙传感器蛋白-1 （NCS-1）的活性及其在肥胖代谢应激反应中的作用。它涉及激活c-Jun nh2末端激酶（JNK）的混合谱系激酶（MLK）途径。使用JNK活性升高的NCS-1敲除（NCS-1-/-）小鼠，以及NCS-1-/-与MLK2/MLK3缺陷（Map3k10-/- Map3k11-/-化合物）小鼠的组合，该建议有三个主要目标：i)揭示NCS-1在NCS-1-/-小鼠肥胖表型中的生理作用；ii)进一步表征NCS-1-/-小鼠的2型糖尿病表型，这与高脂肪饮食下观察到的代谢应激反应的改变有关；iii)探索NCS-1在导致NCS-1-/-小鼠JNK活性增加的混合谱系蛋白激酶途径中的作用。我们期望我们的研究结果有助于更好地理解代谢应激对肥胖反应的调节。

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.