Wu Chia-Shan, Bongmba Odelia Y N, Yue Jing, Lee Jong Han, Lin Ligen, Saito Kenji, Pradhan Geetali, Li De-Pei, Pan Hui-Lin, Xu Allison, Guo Shaodong, Xu Yong, Sun Yuxiang
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA.
United States Department of Agriculture/Agriculture Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Int J Mol Sci. 2017 Apr 14;18(4):832. doi: 10.3390/ijms18040832.
Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (;). Our data showed that GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.
胃饥饿素是一种主要由肠道释放的促食欲激素，它向下丘脑发出信号，刺激生长激素释放，增强食欲并促进体重增加。胃饥饿素受体，即生长激素促分泌素受体（GHS-R），在大脑中高度表达，在下丘脑的刺鼠相关肽（AgRP）神经元中表达最高。我们最近报道，神经元特异性敲除GHS-R可通过激活非寒战产热完全预防小鼠的饮食诱导性肥胖（DIO）。为了进一步破译介导GHS-R代谢作用的特定神经回路，我们构建了AgRP神经元特异性GHS-R基因敲除小鼠（;）。我们的数据表明，AgRP神经元中的GHS-R是胃饥饿素对生长激素分泌、急性食物摄入和肥胖产生刺激作用所必需的，但对长期总食物摄入量并非必需。重要的是，敲除AgRP神经元中的GHS-R可减轻高脂饮食（HFD）喂养小鼠的饮食诱导性肥胖（DIO）并增强其耐寒性。高脂饮食喂养的基因敲除小鼠能量消耗增加，棕色脂肪和皮下脂肪的产热激活均增强；这意味着抑制AgRP神经元中的GHS-R可增强交感神经输出。总之，我们的结果表明，AgRP神经元是GHS-R介导的产热的关键部位，并证明AgRP神经元中的GHS-R在控制能量利用和饮食诱导性肥胖的发病机制中起关键作用。
