Chen Shao-Rui, Chen Hong, Zhou Jing-Jing, Pradhan Geetali, Sun Yuxiang, Pan Hui-Lin, Li De-Pei
Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
J Neurochem. 2017 Aug;142(4):512-520. doi: 10.1111/jnc.14080. Epub 2017 Jun 21.
Ghrelin increases food intake and body weight by stimulating orexigenic agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons and inhibiting anorexic pro-opiomelanocortin (POMC) neurons in the hypothalamus. Growth hormone secretagogue receptor (Ghsr) mediates the effect of ghrelin on feeding behavior and energy homeostasis. However, the role of Ghsr in the ghrelin effect on these two populations of neurons is unclear. We hypothesized that Ghsr mediates the effect of ghrelin on AgRP and POMC neurons. In this study, we determined whether Ghsr similarly mediates the effects of ghrelin on AgRP/NPY and POMC neurons using cell type-specific Ghsr-knockout mice. Perforated whole-cell recordings were performed on green fluorescent protein-tagged AgRP/NPY and POMC neurons in the arcuate nucleus in hypothalamic slices. In Ghsr mice, ghrelin (100 nM) significantly increased the firing activity of AgRP/NPY neurons but inhibited the firing activity of POMC neurons. In Ghsr mice, the excitatory effect of ghrelin on AgRP/NPY neurons was abolished. Ablation of Ghsr also eliminated ghrelin-induced increases in the frequency of GABAergic inhibitory postsynaptic currents of POMC neurons. Strikingly, ablation of Ghsr converted the ghrelin effect on POMC neurons from inhibition to excitation. Des-acylated ghrelin had no such effect on POMC neurons in Ghsr mice. In both Ghsr and Ghsr mice, blocking GABA receptors with gabazine increased the basal firing activity of POMC neurons, and ghrelin further increased the firing activity of POMC neurons in the presence of gabazine. Our findings provide unequivocal evidence that Ghsr is essential for ghrelin-induced excitation of AgRP/NPY neurons. However, ghrelin excites POMC neurons through an unidentified mechanism that is distinct from conventional Ghsr.
胃饥饿素通过刺激下丘脑促食欲的刺鼠相关蛋白（AgRP）/神经肽Y（NPY）神经元并抑制厌食的阿黑皮素原（POMC）神经元，增加食物摄入量和体重。生长激素促分泌素受体（Ghsr）介导胃饥饿素对摄食行为和能量稳态的作用。然而，Ghsr在胃饥饿素对这两类神经元的作用中所起的作用尚不清楚。我们假设Ghsr介导胃饥饿素对AgRP和POMC神经元的作用。在本研究中，我们使用细胞类型特异性Ghsr基因敲除小鼠，确定Ghsr是否同样介导胃饥饿素对AgRP/NPY和POMC神经元的作用。对下丘脑切片弓状核中绿色荧光蛋白标记的AgRP/NPY和POMC神经元进行穿孔全细胞记录。在野生型Ghsr小鼠中，胃饥饿素（100 nM）显著增加AgRP/NPY神经元的放电活动，但抑制POMC神经元的放电活动。在Ghsr基因敲除小鼠中，胃饥饿素对AgRP/NPY神经元的兴奋作用被消除。Ghsr基因的缺失也消除了胃饥饿素诱导的POMC神经元GABA能抑制性突触后电流频率的增加。引人注目的是，Ghsr基因的缺失将胃饥饿素对POMC神经元的作用从抑制转变为兴奋。去酰基化胃饥饿素对Ghsr基因敲除小鼠的POMC神经元没有这种作用。在野生型Ghsr和Ghsr基因敲除小鼠中，用荷包牡丹碱阻断GABA受体均增加了POMC神经元的基础放电活动，并且在存在荷包牡丹碱的情况下，胃饥饿素进一步增加了POMC神经元的放电活动。我们的研究结果提供了明确的证据，表明Ghsr对于胃饥饿素诱导的AgRP/NPY神经元兴奋至关重要。然而，胃饥饿素通过一种不同于传统Ghsr的未知机制兴奋POMC神经元。
