Gastrointestinal Disease Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada.
J Physiol. 2019 Mar;597(6):1487-1502. doi: 10.1113/JP276894. Epub 2018 Dec 18.
Obesity is associated with disrupted satiety regulation. Mice with diet-induced obesity have reduced vagal afferent neuronal excitability and a decreased afferent response to satiety signals. A low grade inflammation occurs in obesity with increased expression of inducible nitric oxide synthase (iNOS). Inhibition of iNOS in diet-induced obese mice restored vagal afferent neuronal excitability, increased the afferent response to satiety mediators and distention of the gut, and reduced short-term energy intake. A prolonged inhibition of iNOS reduced energy intake and body weight gain during the first week, and reduced amounts of epididymal fat after 3 weeks. We identified a novel pathway underlying disrupted satiety regulation in obesity. Blocking of this pathway might be clinically useful for the management of obesity.
Vagal afferents regulate feeding by transmitting satiety signals to the brain. Mice with diet-induced obesity have reduced vagal afferent sensitivity to satiety signals. We investigated whether inducible nitric oxide synthase (iNOS)-derived NO contributed to this reduction. C57BL/6J mice were fed a high- or low-fat diet for 6-8 weeks. Nodose ganglia and jejunum were analysed by immunoblotting for iNOS expression; NO production was measured using a fluorometric assay. Nodose neuron excitability and intestinal afferent sensitivity were evaluated by whole-cell patch clamp and in vitro afferent recording, respectively. Expression of iNOS and production of NO were increased in nodose ganglia and the small intestine in obese mice. Inhibition of iNOS in obese mice by pre-treatment with an iNOS inhibitor increased nodose neuron excitability via 2-pore-domain K channel leak currents, restored afferent sensitivity to satiety signals and reduced short-term energy intake. Obese mice given the iNOS inhibitor daily for 3 weeks had reduced energy intake and decreased body weight gain during the first week, compared to mice given saline, and lower amounts of epididymal fat at the end of 3 weeks. Inhibition of iNOS or blocking the action of iNOS-derived NO on vagal afferent pathways might comprise therapeutic strategies for hyperphagia and obesity.
肥胖与饱腹感调节紊乱有关。饮食诱导肥胖的小鼠迷走传入神经元兴奋性降低，对饱腹感信号的传入反应减弱。肥胖时会发生低度炎症，诱导型一氧化氮合酶 (iNOS) 的表达增加。在饮食诱导肥胖的小鼠中抑制 iNOS 可恢复迷走传入神经元兴奋性，增加饱腹感介质和肠道扩张的传入反应，并减少短期能量摄入。iNOS 的长期抑制可减少第一周的能量摄入和体重增加，并减少 3 周后的附睾脂肪量。我们确定了肥胖症中饱腹感调节紊乱的新途径。阻断该途径可能对肥胖症的治疗具有临床意义。
迷走传入神经通过向大脑传递饱腹感信号来调节进食。饮食诱导肥胖的小鼠对饱腹感信号的迷走传入敏感性降低。我们研究了诱导型一氧化氮合酶 (iNOS) 衍生的 NO 是否有助于这种降低。C57BL/6J 小鼠喂食高脂肪或低脂肪饮食 6-8 周。通过免疫印迹分析迷走神经节和空肠中的 iNOS 表达；使用荧光测定法测量 NO 产生。通过全细胞膜片钳和体外传入记录分别评估迷走神经元兴奋性和肠道传入敏感性。肥胖小鼠的迷走神经节和小肠中 iNOS 的表达和 NO 的产生增加。在肥胖小鼠中，用 iNOS 抑制剂预处理抑制 iNOS 可通过双孔钾通道泄漏电流增加迷走神经元兴奋性，恢复对饱腹感信号的传入敏感性，并减少短期能量摄入。与给予生理盐水的小鼠相比，给予 iNOS 抑制剂的肥胖小鼠在第 3 周的前一周内能量摄入减少，体重增加减少，第 3 周结束时附睾脂肪量减少。抑制 iNOS 或阻断 iNOS 衍生的 NO 对迷走传入途径的作用可能构成治疗贪食症和肥胖症的策略。
