Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain
Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain
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DOI：
10.1016/j.molmet.2019.01.001
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发表时间：
2019-01
影响因子：
8.1
通讯作者：
K. Wardelmann;S. Blümel;M. Rath;E. Alfine;C. Chudoba;M. Schell;Weikang Cai;R. Hauffe;K. Warnke;T. Flore;K. Ritter;J. Weiss;C. Kahn;A. Kleinridders
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文献类型：
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作者：
K. Wardelmann;S. Blümel;M. Rath;E. Alfine;C. Chudoba;M. Schell;Weikang Cai;R. Hauffe;K. Warnke;T. Flore;K. Ritter;J. Weiss;C. Kahn;A. Kleinridders
胰岛素在大脑中的作用控制新陈代谢和大脑功能，这与适当的线粒体功能有关。相反，脑胰岛素抵抗与线粒体应激、代谢和神经退行性疾病相关。在本研究中，我们的目的是解密的影响下丘脑胰岛素作用对线粒体的应激反应，功能和metabolis.MethodsTo研究胰岛素作用和线粒体应激反应（MSR），即线粒体未折叠蛋白反应（UPRmt）和整合的应激反应（ISR）的串扰，qPCR，蛋白质印迹，和线粒体活性测定。这些方法用于分析在存在或不存在胰岛素受体的情况下用胰岛素处理的下丘脑细胞系CLU 183，以及在喂食高脂肪饮食（HFD）三天的小鼠中和在没有或有胰岛素治疗的情况下STZ处理的小鼠中。鼻内胰岛素治疗被用来调查急性脑胰岛素作用对代谢和线粒体stress responses.ResultsAcute HFD喂养降低C57 BL/6 N小鼠下丘脑线粒体应激反应基因Atf 4，Chop，HSP 60，HSP 10，ClpP，和Lonp 1的表达。我们发现，胰岛素通过ERK激活增加MSR基因的表达在体外以及在下丘脑的链脲佐菌素治疗的小鼠。这种调节通过控制线粒体蛋白质稳态来传播线粒体功能，并防止血清剥夺下的过度自噬。最后，短期鼻内胰岛素治疗激活MSR基因表达HFD喂养的C57 BL/6 N小鼠下丘脑，减少食物摄入量和体重development.ConclusionsWe定义下丘脑胰岛素作用作为一种新的主调节MSR，通过控制线粒体蛋白质稳态和调节代谢，确保适当的线粒体功能。
ObjectiveInsulin action in the brain controls metabolism and brain function, which is linked to proper mitochondrial function. Conversely, brain insulin resistance associates with mitochondrial stress and metabolic and neurodegenerative diseases. In the present study, we aimed to decipher the impact of hypothalamic insulin action on mitochondrial stress responses, function and metabolism.MethodsTo investigate the crosstalk of insulin action and mitochondrial stress responses (MSR), namely the mitochondrial unfolded protein response (UPRmt) and integrated stress response (ISR), qPCR, western blotting, and mitochondrial activity assays were performed. These methods were used to analyze the hypothalamic cell line CLU183 treated with insulin in the presence or absence of the insulin receptor as well as in mice fed a high fat diet (HFD) for three days and STZ-treated mice without or with insulin therapy. Intranasal insulin treatment was used to investigate the effect of acute brain insulin action on metabolism and mitochondrial stress responses.ResultsAcute HFD feeding reduces hypothalamic mitochondrial stress responsive gene expression ofAtf4,Chop,Hsp60,Hsp10,ClpP, andLonp1in C57BL/6N mice. We show that insulin via ERK activation increases the expression of MSR genesin vitroas well as in the hypothalamus of streptozotocin-treated mice. This regulation propagates mitochondrial function by controlling mitochondrial proteostasis and prevents excessive autophagy under serum deprivation. Finally, short-term intranasal insulin treatment activates MSR gene expression in the hypothalamus of HFD-fed C57BL/6N mice and reduces food intake and body weight development.ConclusionsWe define hypothalamic insulin action as a novel master regulator of MSR, ensuring proper mitochondrial function by controlling mitochondrial proteostasis and regulating metabolism.