Kentish S J, O'Donnell T A, Frisby C L, Li H, Wittert G A, Page A J
Nerve-Gut Research Laboratory, Hanson Institute, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
Royal Adelaide Hospital, Adelaide, SA, Australia.
Int J Obes (Lond). 2014 May;38(5):636-42. doi: 10.1038/ijo.2013.138. Epub 2013 Jul 30.
Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD).
Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach.
After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice.
Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss.
胃迷走传入神经在对机械刺激作出反应时传递饱腹感信号。在饮食诱导的肥胖中，这些传入神经的敏感性降低。胃上皮细胞分泌的瘦素可增强瘦小鼠迷走传入神经对机械刺激的反应，但对高脂饮食（HFD）诱导的肥胖小鼠具有抑制作用。我们试图确定肥胖小鼠迷走传入神经功能的变化以及对瘦素的反应是否可通过将食用HFD的肥胖小鼠恢复至标准实验室饲料饮食（SLD）而逆转。
8周龄雌性C57BL/6小鼠分别喂食SLD（N = 20）或HFD（N = 20）24周。第三组先喂食HFD 12周，然后再喂食SLD 12周（RFD，N = 18）。采用体外胃-食管迷走传入神经制备方法来确定胃迷走传入神经的机械敏感性，并检测瘦素（0.1 - 10 nM）的调节作用。采用逆行追踪和定量RT-PCR来确定整个结状神经节以及从胃追踪到的特定细胞体中瘦素受体（LepR）信使核糖核酸（mRNA）的表达。
24周后，与SLD小鼠相比，HFD和RFD小鼠的体重、性腺脂肪量、血浆瘦素、血浆胰岛素和每日能量消耗均增加。HFD和RFD小鼠的张力受体机械敏感性降低，瘦素进一步抑制HFD、RFD小鼠而非SLD小鼠对张力的反应。瘦素增强了SLD和RFD小鼠的黏膜受体反应，而HFD小鼠未出现这种效应。LepR在整个结状神经节中的表达未发生变化，但在HFD和RFD小鼠的黏膜传入神经中表达降低。
HFD诱导的肥胖对胃迷走传入神经功能的破坏仅通过饮食改变部分可逆，这为防止体重减轻的维持提供了一种潜在机制。
