Mechanisms and physiological roles of regulation of orexin-producing neurons by leptin and TNF-alfa

瘦素是一种脂肪组织衍生激素，在维持能量平衡方面起着重要作用。瘦素调节下丘脑神经元的活性和神经元中的基因表达。已有研究报道瘦素可抑制或激活下丘脑弓状神经元，但具体机制尚不清楚。瘦素对其他下丘脑核，特别是下丘脑外侧核(例如表达食欲素的神经元)的影响尚不清楚，食欲素也是能量调节的关键。我们研究了瘦素对这些下丘脑神经元的调节机制。我们通过对表达绿色荧光蛋白的神经元进行膜片钳记录，检测了瘦素对下丘脑神经元的影响。瘦素使增食欲素和神经肽Y神经元超极化，在PI3K或JAK2抑制剂的存在下，这两种反应都被完全抑制。此外，KATP通道阻断剂甲苯丁胺可完全消除瘦素引起的超极化。我们还发现，另一种脂肪细胞衍生因子，肿瘤坏死因子-α抑制了食欲素产生的神经元。这种作用在PI3K抑制剂的存在下也被完全消除。这些机制可能对下丘脑神经元的生理调节，特别是对能量平衡和睡眠/觉醒的协调具有重要意义。

An adipose tissue derived hormone, leptin plays a role in the maintenance of the energy homeostasis. Leptin regulates the hypothalamic neurons activity and gene expression in the neurons. It has been already reported that leptin inhibited or activated hypothalamic arcuate neurons, but the detail mechanism remains to be unknown. Effects of leptin on other hypothalamic nucleus, especially lateral hypothalamic (LH) neurons, such as ones that express orexins, which are also crucial for energy regulation, have been yet unclear. We examined the mechanisms which underlie the leptin-induced regulation of these hypothalamic neurons.We examined the effects of leptin on the hypothalamic neurons by patch-clamp recording from EGFP-expressing neurons. Leptin hyperpolarized orexin and NPY neurons, and both of the responses was completely inhibited in the presence of the PI3K inhibitor or JAK2 inhibitor. Furthermore, tolbutamide, which is a blocker of KATP channels, completely abolished the leptin-induced hyperpolarization. We also found that another adipocyte derived factor, TNF-alfa inhibits orexin-producing neurons. This effect was also completely abolished in the presence of the PI3K inhibitor. These mechanisms might be important for the physiological regulation of hypothalamic neurons, especially for the coordination of energy balance as well as sleep/wakefulness.