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

胰腺来源的激素胰岛素和脂肪分泌的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都有表达，并通过中枢激活它们的通路来控制新陈代谢和认知功能。这两种激素不仅表现出相似的生理功能，如调节食物摄入量，还在分子水平上交叉激活各自的信号通路。胰岛素和瘦素抵抗是代谢紊乱的特征。因此，过去十年的研究一直集中在了解中枢性胰岛素和瘦素抵抗的发生和后果。这导致了内质网未折叠蛋白反应(UPRer)对代谢的影响的发现。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的蛋白质负担以及增加错误折叠蛋白质的降解来恢复细胞内的动态平衡。内质网伴侣蛋白的减少改善了胰岛素和瘦素信号，而这一通路的过度激活则导致中枢胰岛素和瘦素抵抗。因此，在糖尿病的各种组织中观察到ER伴侣蛋白的表达增加。除了UPRer，还有线粒体的UPR(UPRmt)。这种应激反应是一种线粒体到核的信号转导途径，诱导线粒体保护性基因，包括线粒体蛋白酶和伴侣基因，如Hsp60和Hsp10，重建线粒体内蛋白质的动态平衡。UPRmt对新陈代谢的影响还知之甚少。线粒体功能障碍与活性氧(ROS)生成增加和胰岛素抵抗有关，但线粒体伴侣蛋白，尤其是Hsp60对胰岛素信号转导的影响是最近才被证实的。UPRmt的代谢调节及其对下丘脑瘦素信号的影响尚不清楚。虽然氧化应激导致胰岛素抵抗，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，因为线粒体的其他功能必须恢复。线粒体对脂肪酸代谢也是至关重要的，其中关键酶的折叠，如MCAD是由Hsp60和Hsp10催化的。因此，有人认为UPRmt的改变将影响下丘脑的脂肪酸代谢和胰岛素敏感性，因为脂肪酸代谢产物如酰肉碱可以诱导胰岛素抵抗。本研究旨在探讨脑内线粒体UPR的代谢调节，b)线粒体伴侣对瘦素信号的影响，以及c)UPRmt异常对下丘脑脂肪酸代谢和中枢胰岛素敏感性的影响。

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.