Institute of Veterinary Physiology and Centre of Integrative Human Physiology, University of Zurich, 8057 Zurich, Switzerland.
Brain Behav Immun. 2012 Aug;26(6):867-79. doi: 10.1016/j.bbi.2012.03.005. Epub 2012 Mar 23.
Lipopolysaccharide (LPS) induces anorexia and expression of inducible nitric oxide synthase (iNOS) in the hypothalamic arcuate nucleus (Arc). Peripheral administration of the iNOS inhibitor 1400 W counteracts the anorectic effects of LPS. Here we investigated the role of central NO signaling in LPS anorexia. In electrophysiological studies we tested whether 1400 W counteracts the iNOS-dependent inhibition of Arc neurons triggered by in vivo or in vitro stimulation with LPS. We used the hormone ghrelin as a functional reference stimulus because ghrelin is known to activate orexigenic Arc neurons. Further, we investigated whether in vitro LPS stimulation induces an iNOS-mediated formation of the second messenger cGMP. Since the STAT1 pathway contributes to the regulation of iNOS expression we investigated whether LPS treatment induces STAT1 phosphorylation in the Arc. Finally we tested the effect of intracerebroventricular injection of 1400 W on LPS-induced anorexia. Superfusion with 1400 W (10(-4) M) increased neuronal activity in 37% of neurons in Arc slices from LPS treated (100 μg/kg ip) but not from saline treated rats. Similarly, 1400 W excited 45% of Arc neurons after in vitro stimulation with LPS (100 ng/ml). In both approaches, a considerable percentage of 1400 W sensitive neurons were excited by ghrelin (10(-8)M; 50% and 75%, respectively). In vitro stimulation with LPS induced cGMP formation in the Arc, which was blocked by co-incubation with 1400 W. LPS treatment elicited a pSTAT1 response in the Arc of mice. Central 1400 W injection (4 μg/rat) attenuated LPS-induced anorexia and counteracted the LPS-dependent decrease in respiratory quotient and energy expenditure. In conclusion, the current findings substantiate a role of central iNOS dependent NO formation in LPS-induced effects on eating and energy homeostasis. A pharmacological blockade of NO formation might be a therapeutic approach to ameliorate disease-related anorexia.
脂多糖（LPS）可诱导下丘脑弓状核（Arc）中食欲素和诱导型一氧化氮合酶（iNOS）的表达。外周给予 iNOS 抑制剂 1400 W 可拮抗 LPS 的致厌食作用。在此，我们研究了中枢 NO 信号在 LPS 致厌食中的作用。在电生理学研究中，我们测试了 1400 W 是否拮抗由 LPS 体内或体外刺激引发的 Arc 神经元中 iNOS 依赖性抑制作用。我们使用激素 ghrelin 作为功能参考刺激物，因为已知 ghrelin 可激活食欲素能的 Arc 神经元。此外，我们研究了体外 LPS 刺激是否诱导第二信使 cGMP 的 iNOS 介导形成。由于 STAT1 途径有助于 iNOS 表达的调节，因此我们研究了 LPS 处理是否诱导 Arc 中 STAT1 的磷酸化。最后，我们测试了脑室注射 1400 W 对 LPS 诱导的厌食症的影响。1400 W（10（-4）M）的灌流增加了来自 LPS 处理（100μg/kg ip）而非盐水处理大鼠的 Arc 切片中 37％神经元的神经元活性。同样，1400 W 刺激离体 LPS（100ng/ml）后兴奋了 45％的 Arc 神经元。在这两种方法中，相当一部分对 1400 W 敏感的神经元都被 ghrelin 兴奋（10（-8）M；分别为 50％和 75％）。体外刺激 LPS 诱导 Arc 中 cGMP 的形成，这可被与 1400 W 共孵育阻断。LPS 处理引发了小鼠 Arc 中的 pSTAT1 反应。中枢注射 1400 W（4μg/rat）可减轻 LPS 诱导的厌食症，并拮抗 LPS 依赖性呼吸商和能量消耗的降低。总之，目前的研究结果证实了中枢 iNOS 依赖性 NO 形成在 LPS 诱导的进食和能量稳态中的作用。NO 形成的药理学阻断可能是改善疾病相关厌食症的一种治疗方法。
