瘦素是一种在能量代谢、生育能力等多方面起关键作用的激素,日前哥伦比亚大学医学中心CUMC的一项新研究显示,瘦素还能够调控呼吸道直径。这一发现有助于解释过于肥胖的人容易患哮喘的原因,并提出抑制副交感神经系统信号的药物能够通过调节瘦素功能,来缓解体重相关的哮喘。这项研究在小鼠中进行,发表在Cell旗下的Cell Metabolism杂志上。
“我们的研究是基于,在临床观察中发现肥胖症和厌食症都可能引起哮喘,” CUMC医学教授Gerard Karsenty说。“这样的现象使我们推测,应该有来自脂肪细胞的某种信号直接或间接的影响了肺部。”而瘦素是最有可能的蛋白,它由脂肪细胞产生在血流中循环并能够到达脑部。
有大量证据显示,肥胖会导致呼吸道狭窄(bronchoconstriction),当哮喘病人患上肥胖症时,病情就会加剧并且会影响哮喘的治疗,只不过人们此前还并不清楚其中的机理。这项研究首次阐明了肥胖症、呼吸道直径和肺部功能之间的分子关联。
研究人员通过小鼠实验发现,体重、脂肪含量过高或过低都会导致呼吸道狭窄和肺部功能减弱,而且瘦素能够增加呼吸道直径。研究显示,瘦素通过抑制副交感神经系统的活性影响呼吸道,而这一系统并不经常与瘦素联系起来。研究人员还发现不论支气管是否存在局部炎症,瘦素对呼吸道直径的调控都会发生。
研究人员选择肥胖且患有哮喘的小鼠,对其施以增加肺部炎症的药物。随后他们向小鼠大脑注入瘦素四天,“这对于炎症没有影响,但呼吸道直径和肺部功能都恢复正常了,” Dr. Karsenty说。“这说明我们可以在不影响炎症的情况下,在小鼠中治愈肥胖相关的哮喘。”他们又用降低副交感神经系统信号传导的药物治疗肥胖且哮喘的小鼠,数日后哮喘同样得到了缓解。
“这告诉我们,用抑制副交感神经系统信号传导的药物来促进瘦素的作用,有望治疗肥胖相关的哮喘症。” Dr. Karsenty说。现实中也的确存在这样的药物,例如主要被用于诊断支气管高反应性的methacholine等。(生物谷Bioon.com)
DOI:10.1016/j.cmet.2012.12.004
PMC:
PMID:
Inhibition of Leptin Regulation of Parasympathetic Signaling as a Cause of Extreme Body Weight-Associated Asthma
Emilio Arteaga-Solis, Tiffany Zee, Charles W. Emala, Charles Vinson, Jürgen Wess, Gerard Karsenty
Impaired lung function caused by decreased airway diameter (bronchoconstriction) is frequently observed whether body weight is abnormally high or low. That these opposite conditions affect the airways similarly suggests that the regulation of airway diameter and body weight are intertwined. We show here that, independently of its regulation of appetite, melanocortin pathway, or sympathetic tone, leptin is necessary and sufficient to increase airway diameter by signaling through its cognate receptor in cholinergic neurons. The latter decreases parasympathetic signaling through the M3 muscarinic receptor in airway smooth muscle cells, thereby increasing airway diameter without affecting local inflammation. Accordingly, decreasing parasympathetic tone genetically or pharmacologically corrects bronchoconstriction and normalizes lung function in obese mice regardless of bronchial inflammation. This study reveals an adipocyte-dependent regulation of bronchial diameter whose disruption contributes to the impaired lung function caused by abnormal body weight. These findings may be of use in the management of obesity-associated asthma.