Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Cologne, Germany.
Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
Nat Commun. 2021 Sep 2;12(1):5249. doi: 10.1038/s41467-021-25380-2.
The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.
觉醒激活的食欲素系统在动态调节葡萄糖稳态中发挥核心作用。在这里，我们发现食欲素受体 1 和 2 主要在中缝背核背侧和腹侧表达。中缝正中核和苍白球中的 5-羟色胺能神经元选择性表达食欲素受体 1。在表达血清素转运蛋白的小鼠中敲除食欲素受体 1 会降低饮食诱导肥胖小鼠的胰岛素敏感性，主要是通过减少棕色脂肪组织和骨骼肌中的葡萄糖利用。选择性敲除食欲素受体 2 可改善肥胖小鼠的葡萄糖耐量和胰岛素敏感性，主要是通过减少肝糖异生。外侧下丘脑的食欲素神经元或投射到苍白球的食欲素能纤维的光遗传学激活分别损害或改善葡萄糖耐量。总的来说，本研究表明，5-羟色胺能神经元中的食欲素信号传递具有重要作用，但在调节全身葡萄糖稳态方面，食欲素受体 1 和 2 具有不同的功能。
