Hurtado-Carneiro Verónica, Roncero Isabel, Egger Sascha S, Wenger Roland H, Blazquez Enrique, Sanz Carmen, Alvarez Elvira
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Plaza S. Ramón y Cajal, s/n, Madrid, 28040, Spain,
Mol Neurobiol. 2014 Oct;50(2):314-26. doi: 10.1007/s12035-013-8630-4. Epub 2014 Jan 21.
The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity. We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/re-feeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and the anorexigenic properties of exendin-4 were significantly reduced, suggesting that PASK could be a mediator in the GLP-1 signalling pathway. Our data indicated that the PASK function could be critical for preserving the nutrient effect on AMPK and mTOR/S6K1 pathways and maintain the regulatory role of exendin-4 in food intake. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes.
超重、肥胖和2型糖尿病引发的并发症是发达国家发病率和死亡率上升的主要问题之一。下丘脑代谢传感器在进食控制和能量稳态中发挥着重要作用。PAS激酶（PASK）是一种营养传感器，被认为是葡萄糖代谢和细胞能量的调节剂。PASK的作用可能与其他已知的代谢传感器类似，如AMP激活的蛋白激酶（AMPK）和雷帕霉素哺乳动物靶蛋白（mTOR）。PASK基因缺陷的小鼠对饮食诱导的肥胖具有抵抗力。我们最近报道，在营养状态的影响下，AMPK和mTOR/S6K1信号通路在下丘脑腹内侧核和外侧核中受到调节，在瘦鼠和肥胖大鼠中受厌食性胰高血糖素样肽-1（GLP-1）/艾塞那肽-4的调控。我们在下丘脑区域鉴定出了PASK，其表达在禁食/再进食条件下受到调节，并受艾塞那肽-4的调控。此外，PASK基因缺陷的小鼠的AMPK和mTOR/S6K1信号通路的激活反应受损。因此，下丘脑AMPK和S6K1在禁食/再进食条件下被高度激活。此外，在本研究中，我们观察到在PASK基因缺陷的小鼠中，艾塞那肽-4对代谢传感器活性的调节作用丧失，且艾塞那肽-4的厌食特性显著降低，这表明PASK可能是GLP-1信号通路中的一种介质。我们的数据表明，PASK功能对于维持营养物质对AMPK和mTOR/S6K1信号通路的作用以及维持艾塞那肽-4在食物摄入中的调节作用可能至关重要。艾塞那肽-4的一些抗糖尿病作用可能通过这些过程来调节。
