Neuronal GHS-R Differentially Modulates Feeding Patterns under Normal and Obesogenic Conditions.
Neuronal GHS-R Differentially Modulates Feeding Patterns under Normal and Obesogenic Conditions.
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DOI：
10.3390/biom12020293
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发表时间：
2022-02-11
期刊：
影响因子：
5.5
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Lee JH;Xue B;Chen Z;Sun Y
促食欲激素胃饥饿素通过其受体生长激素促分泌素受体 (GHS-R) 增加食物摄入量并促进肥胖。我们之前报道了两种神经元特异性 GHS-R 敲除小鼠系，即 Syn1-cre 的全神经元缺失和 AgRP-cre 的下丘脑缺失，表现出不同的饮食依赖性对体重的影响。与高脂肪饮食 (HFD) 相比，神经元 GHS-R 缺乏在常规饮食 (RD) 下引起的代谢影响不太明显。虽然 Syn1-cre 小鼠品系的 HFD 总食物摄入量没有差异； Ghsrf/f小鼠表现出比AgRP-cre更强的抗肥胖作用； Ghsrf/f 小鼠。众所周知，膳食喂养模式对能量稳态和肥胖发展有重大影响。在这里，我们通过评估进餐次数、进餐量、进餐时间和进食频率，研究了这两只神经元特异性 GHS-R 敲除小鼠在 RD 和 HFD 喂养下的进食行为。正常饮食下，RD喂养Syn1-cre； Ghsrf/f 小鼠在黑暗阶段表现出膳食量减少，而 RD 喂养的 AgRP-cre 小鼠则表现出膳食量减少； Ghsrf/f 小鼠在黑暗阶段的进餐时间延长。在致肥饮食下，HFD 喂养 Syn1-cre； Ghsrf/f 小鼠在光照阶段的进食次数减少，在光照和黑暗阶段的进食次数增加，而 HFD 喂养的 AgRP-cre 小鼠则表现出增加的进食量。 Ghsrf/f 小鼠仅在光照阶段表现出进餐时间缩短。一致地，喂食 RD 的 Syn1-cre 的下丘脑中神经肽（神经肽 Y 和食欲素）的表达增加； Ghsrf/f 小鼠，而喂食 Syn1-cre 的 HFD 小鼠下丘脑中 1 型大麻素受体 (CB1) 的表达增加； Ghsrf/f 小鼠。总体而言，Syn1-cre 的喂养方式变化更为明显； Ghsrf/f小鼠与AgRP-cre小鼠相比； Ghsrf/f 小鼠和 HFD 比 RD 引起更大的改变。而AgRP-cre； Ghsrf/f 小鼠白天消耗 HFD 食物的速度更快（显示进餐时间更短），Syn1-cre； Ghsrf/f 小鼠在浅色阶段吃很少的 HFD 餐，并且全天吃得很慢（在两个阶段都显示出更长的进餐时间）。我们的研究结果表明，神经元 GHS-R 通过改变进食模式来调节能量稳态，并以位点和饮食依赖性方式差异调节进食模式。这两个小鼠品系的独特数据还表明，在最佳喂养期（小鼠的黑暗期）缓慢进食可能有利于对抗肥胖。
The orexigenic hormone ghrelin increases food intake and promotes obesity through its receptor, growth hormone secretagogue receptor (GHS-R). We previously reported two neuron-specific GHS-R knockout mouse lines, namely pan-neuronal deletion by Syn1-cre and hypothalamic deletion by AgRP-cre, exhibiting differential diet-dependent effects on body weight. GHS-R deficiency in neurons elicited less pronounced metabolic effects under regular diet (RD) than high fat diet (HFD). While there was no difference in total food intake of HFD in either mouse line, Syn1-cre; Ghsrf/f mice showed much greater anti-obesity effect than that of AgRP-cre; Ghsrf/f mice. Meal feeding pattern is known to have a major impact on energy homeostasis and obesity development. Here, we investigated the feeding behaviors of these two neuron-specific GHS-R knockout mice under RD and HFD feeding, by assessing meal number, meal size, meal duration, and feeding frequency. Under the normal diet, RD-fed Syn1-cre; Ghsrf/f mice showed a decreased meal size in dark phase, while RD-fed AgRP-cre; Ghsrf/f mice showed an increased meal duration in dark phase. Under the obesogenic diet, HFD-fed Syn1-cre; Ghsrf/f mice displayed reduced meal numbers in light phase and increased feeding in both light and dark phases, whereas HFD-fed AgRP-cre; Ghsrf/f mice showed a decreased meal duration in the light phase only. Consistently, the expression of neuropeptides (Neuropeptide Y and Orexin) was increased in the hypothalamus of RD-fed Syn1-cre; Ghsrf/f mice, whereas the expression of cannabinoid receptor type 1 (CB1) was increased in the hypothalamus of HFD fed Syn1-cre; Ghsrf/f mice. Overall, feeding pattern changes were more pronounced in Syn1-cre; Ghsrf/f mice than that in AgRP-cre; Ghsrf/f mice, and HFD elicited greater alteration than RD. While AgRP-cre; Ghsrf/f mice consumed HFD meals faster during the day (showing shorter meal duration), Syn1-cre; Ghsrf/f mice ate few HFD meals during the light phase and ate slowly throughout the day (showing longer meal duration in both phases). Our findings reveal that neuronal GHS-R regulates energy homeostasis by altering feeding patterns, and differentially modulates feeding patterns in a site- and diet-dependent manner. The distinctive data in these two mouse lines also suggest that eating slowly during the optimal feeding period (dark phase for mice) may be beneficial in combating obesity.
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