Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Department of Internal Medicine, Chungnam National University Hospital, Daejeon, South Korea.
PLoS Biol. 2023 Aug 18;21(8):e3002252. doi: 10.1371/journal.pbio.3002252. eCollection 2023 Aug.
It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function. Here, we found that the G protein-gated inwardly rectifying K+ (GIRK) channels are key to stabilize NPY/AgRP neurons and that NPY/AgRP neuron-selective deletion of the GIRK2 subunit results in a persistently increased excitability of the NPY/AgRP neurons. Interestingly, increased body weight and adiposity observed in the NPY/AgRP neuron-selective GIRK2 knockout mice were due to decreased sympathetic activity and EE, while food intake remained unchanged. The conditional knockout mice also showed compromised adaptation to coldness. In summary, our study identified GIRK2 as a key determinant of NPY/AgRP neuronal excitability and driver of EE in physiological and stress conditions.
众所周知，神经肽 Y（NPY）/刺鼠相关肽（AgRP）神经元会增加食欲并减少产热。先前的研究表明，对 NPY/AgRP 神经元活性进行光遗传学和/或化学遗传学操作会改变食物摄入和/或能量消耗（EE）。然而，对于调节 NPY/AgRP 神经元兴奋性以影响长期代谢功能的内在分子知之甚少。在这里，我们发现 G 蛋白门控内向整流钾（GIRK）通道是稳定 NPY/AgRP 神经元的关键，并且 NPY/AgRP 神经元选择性缺失 GIRK2 亚基会导致 NPY/AgRP 神经元的兴奋性持续增加。有趣的是，在 NPY/AgRP 神经元选择性 GIRK2 敲除小鼠中观察到的体重和肥胖增加是由于交感神经活动和 EE 减少所致，而食物摄入量保持不变。条件性敲除小鼠也表现出对寒冷的适应能力受损。总之，我们的研究确定 GIRK2 是 NPY/AgRP 神经元兴奋性的关键决定因素，也是生理和应激条件下 EE 的驱动因素。
