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Metabolic Regulation of Hsp60/Hsp10 Chaperone Complex Impacts on Hypothalamic Lipid Metabolism

Hsp60/Hsp10 伴侣复合物的代谢调节对下丘脑脂质代谢的影响

基本信息

批准号：
287329768
负责人：
Professor Dr. André Kleinridders
金额：
--
依托单位：
Institut für Ernährungswissenschaft
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/287329768?language=en
关键词：
Metabolic Regulation Hsp60 Hsp10 Chaperone

项目摘要

The pancreas-derived hormone insulin and the fat-secreted hormone leptin are key metabolic hormones. Receptors for both hormones are expressed throughout the brain and control metabolism and cognitive function via central activation of their pathways. Both hormones exhibit not only similar physiological function, such as regulating food intake, they also crossactivate their signaling pathways on a molecular level. Insulin and leptin resistance are hallmarks of metabolic disorders. Thus, research over the last decade has been focused on understanding the occurrence and consequences of central insulin and leptin resistance. This led to the discovery of the influence of unfolded protein response of the endoplasmatic reticulum (UPRer) on metabolism. This stress response aims to restore cellular homeostasis by stopping protein translation, upregulating chaperones to cope with the burden of misfolded proteins and increasing the degradation of misfolded proteins. A reduction of ER chaperones improves insulin and leptin signaling, whereas overactivation of this pathway induces central insulin and leptin resistance. Thus, increased expression of ER chaperones in diabetic conditions has been observed in a variety of tissues.In addition to UPRer, there is also an UPR of the mitochondria (UPRmt). This stress response is a mitochondria-to-nuclear signal transduction pathway inducing mitochondrial protective genes including mitochondrial proteases and chaperones, such as Hsp60 and Hsp10, to re-establish protein homeostasis within the mitochondria. The effect of UPRmt on metabolism is poorly understood. Mitochondrial dysfunction has been associated with an increased production of reactive oxygen species (ROS) and insulin resistance, yet the effect of mitochondrial chaperones, especially Hsp60, on insulin signaling was demonstrated just recently. The metabolic regulation of the UPRmt and its effect on hypothalamic leptin signaling is unknown. Although oxidative stress induces insulin resistance, antioxidants failed in reversing insulin resistance in clinics. One hypothesis is that just reducing oxidative stress is not sufficient enough to restore insulin signaling, as other features of mitochondrial function have to be restored. Mitochondria are also crucial for fatty acid metabolism, where folding of key enzymes such as MCAD is catalyzed by Hsp60 and Hsp10. Thus, it is proposed that an altered UPRmt will affect hypothalamic fatty acid metabolism and insulin sensitivity, as fatty acid metabolites such as acylcarnitines can induce insulin resistance.This proposal aims to investigate, a) the metabolic regulation of the mitochondrial UPR in the brain, b) the effect of mitochondrial chaperones on leptin signaling and c) the consequence of a dysregulated UPRmt on hypothalamic fatty acid metabolism and central insulin sensitivity.

胰腺源性激素胰岛素和脂肪分泌激素瘦素是关键的代谢激素。这两种激素的受体在整个大脑中表达，并通过中枢激活途径控制代谢和认知功能。这两种激素不仅表现出相似的生理功能，比如调节食物摄入，而且在分子水平上交叉激活它们的信号通路。胰岛素和瘦素抵抗是代谢紊乱的标志。因此，过去十年的研究一直集中在了解中枢胰岛素和瘦素抵抗的发生和后果。这导致发现内质网未折叠蛋白反应（UPRer）对代谢的影响。这种应激反应旨在通过停止蛋白质翻译、上调伴侣蛋白以应对错误折叠蛋白质的负担以及增加错误折叠蛋白质的降解来恢复细胞稳态。内质网伴侣的减少可改善胰岛素和瘦素信号传导，而该途径的过度激活可诱导中枢胰岛素和瘦素抵抗。因此，在糖尿病患者的多种组织中已经观察到ER伴侣蛋白的表达增加。除了UPR，还有线粒体UPR （UPRmt）。这种应激反应是线粒体到核的信号转导途径，诱导包括线粒体蛋白酶和伴侣蛋白（如Hsp60和Hsp10）在内的线粒体保护基因在线粒体内重建蛋白质稳态。UPRmt对代谢的影响尚不清楚。线粒体功能障碍与活性氧（ROS）的产生增加和胰岛素抵抗有关，但线粒体伴侣蛋白，特别是Hsp60，对胰岛素信号传导的影响最近才得到证实。UPRmt的代谢调节及其对下丘脑瘦素信号传导的影响尚不清楚。虽然氧化应激诱导胰岛素抵抗，但抗氧化剂在临床上未能逆转胰岛素抵抗。一种假设是，仅仅减少氧化应激不足以恢复胰岛素信号，因为线粒体功能的其他特征必须恢复。线粒体对脂肪酸代谢也至关重要，其中关键酶如MCAD的折叠是由Hsp60和Hsp10催化的。因此，我们提出upmt的改变会影响下丘脑脂肪酸代谢和胰岛素敏感性，因为脂肪酸代谢物如酰基肉碱可以诱导胰岛素抵抗。本研究旨在研究a)脑内线粒体UPR的代谢调节，b)线粒体伴侣对瘦素信号的影响，以及c) UPR异常对下丘脑脂肪酸代谢和中枢胰岛素敏感性的影响。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

DOI：
10.3389/fendo.2018.00196
发表时间：
2018
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Castro JP;Wardelmann K;Grune T;Kleinridders A
通讯作者：
Kleinridders A

Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain

DOI：
10.1016/j.molmet.2019.01.001
发表时间：
2019-01
期刊：
Molecular Metabolism
影响因子：
8.1
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
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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