Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Biochemistry, Utah Southwestern Medical Center at Dallas, University of Texas Southwestern Medical Center, Dallas, Texas.
Endocrinology. 2019 May 1;160(5):1307-1322. doi: 10.1210/en.2019-00021.
Leptin has been proposed to modulate viscerosensory information directly at the level of vagal afferents. In support of this view, broad expression for the leptin receptor (Lepr) has previously been reported in vagal afferents. However, the exact identity and distribution of leptin-sensitive vagal afferents has not been elucidated. Using quantitative PCR, we found that the whole mouse nodose ganglion was predominantly enriched in the short form of Lepr, rather than its long form. Consistent with this observation, the acute administration of leptin did not stimulate JAK-STAT signaling in the nodose ganglion. Using chromogenic in situ hybridization in wild-type mice and several reporter mouse models, we demonstrated that Lepr mRNA was restricted to nonneuronal cells in the epineurium and parenchyma of the nodose ganglion and a subset of vagal afferents, which accounted for only 3% of all neuronal profiles. Double labeling studies further established that Lepr-expressing vagal afferents were Nav1.8-negative fibers that did not supply the peritoneal cavity. Finally, double chromogenic in situ hybridization revealed that many Lepr-expressing neurons coexpressed the angiotensin 1a receptor (At1ar), which is a gene expressed in baroreceptors. Taken together, our data challenge the commonly held view that Lepr is broadly expressed in vagal afferents. Instead, our data suggest that leptin may exert a previously unrecognized role, mainly via its short form, as a direct modulator of a very small group of At1ar-positive vagal fibers.
瘦素被认为可以直接在迷走传入神经纤维水平上调节内脏感觉信息。支持这一观点的是，先前已经报道瘦素受体（Lepr）在迷走传入神经纤维中有广泛表达。然而，瘦素敏感的迷走传入纤维的确切身份和分布尚未阐明。使用定量 PCR，我们发现整个小鼠结状神经节主要富含 Lepr 的短形式，而不是其长形式。与这一观察结果一致，瘦素的急性给药并没有刺激结状神经节中的 JAK-STAT 信号。通过在野生型小鼠和几种报告小鼠模型中使用显色原位杂交，我们证明 Lepr mRNA 局限于结状神经节的神经外膜和实质中的非神经元细胞以及一部分迷走传入纤维，这些纤维仅占所有神经元形态的 3%。双重标记研究进一步证实，Lepr 表达的迷走传入纤维是 Nav1.8 阴性纤维，不供应腹腔。最后，双重显色原位杂交显示，许多 Lepr 表达神经元共表达血管紧张素 1a 受体（At1ar），这是一种在压力感受器中表达的基因。总之，我们的数据挑战了 Lepr 在迷走传入纤维中广泛表达的普遍观点。相反，我们的数据表明，瘦素可能通过其短形式发挥以前未被认识到的作用，主要作为一小群 At1ar 阳性迷走纤维的直接调节剂。
