Department of Marine Bio and Medical Science, Hanseo University, Seosan 31962, Korea.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Biomolecules. 2022 Feb 11;12(2):293. doi: 10.3390/biom12020293.
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; Ghsr mice showed much greater anti-obesity effect than that of AgRP-cre; Ghsr 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; Ghsr mice showed a decreased meal size in dark phase, while RD-fed AgRP-cre; Ghsr mice showed an increased meal duration in dark phase. Under the obesogenic diet, HFD-fed Syn1-cre; Ghsr mice displayed reduced meal numbers in light phase and increased feeding in both light and dark phases, whereas HFD-fed AgRP-cre; Ghsr 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; Ghsr mice, whereas the expression of cannabinoid receptor type 1 (CB1) was increased in the hypothalamus of HFD fed Syn1-cre; Ghsr mice. Overall, feeding pattern changes were more pronounced in Syn1-cre; Ghsr mice than that in AgRP-cre; Ghsr mice, and HFD elicited greater alteration than RD. While AgRP-cre; Ghsr mice consumed HFD meals faster during the day (showing shorter meal duration), Syn1-cre; Ghsr 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.
食欲激素 ghrelin 通过其受体生长激素促分泌素受体 (GHS-R) 增加食物摄入并促进肥胖。我们之前报道了两种神经元特异性 GHS-R 敲除小鼠品系，即通过 Syn1-cre 的全神经元缺失和通过 AgRP-cre 的下丘脑缺失，它们在体重方面表现出不同的饮食依赖性影响。与高脂肪饮食 (HFD) 相比，神经元中的 GHS-R 缺乏在常规饮食 (RD) 下引起的代谢效应不那么明显。虽然在这两种小鼠品系中，HFD 的总食物摄入量没有差异，但 Syn1-cre;Ghsr 小鼠比 AgRP-cre;Ghsr 小鼠表现出更大的抗肥胖效果。摄食模式已知对能量平衡和肥胖发展有重大影响。在这里，我们通过评估进食次数、进食量、进食持续时间和进食频率，研究了这两种神经元特异性 GHS-R 敲除小鼠在 RD 和 HFD 喂养下的进食行为。在正常饮食下，RD 喂养的 Syn1-cre;Ghsr 小鼠在暗期的进食量减少，而 RD 喂养的 AgRP-cre;Ghsr 小鼠在暗期的进食持续时间增加。在致肥胖饮食下，HFD 喂养的 Syn1-cre;Ghsr 小鼠在光期的进食次数减少，光期和暗期的进食次数增加，而 HFD 喂养的 AgRP-cre;Ghsr 小鼠仅在光期的进食持续时间减少。一致地，RD 喂养的 Syn1-cre;Ghsr 小鼠的下丘脑神经肽（神经肽 Y 和食欲素）表达增加，而 HFD 喂养的 Syn1-cre;Ghsr 小鼠的下丘脑大麻素受体 1 (CB1) 表达增加。总的来说，Syn1-cre;Ghsr 小鼠的摄食模式变化比 AgRP-cre;Ghsr 小鼠更明显，而 HFD 比 RD 引起更大的变化。虽然 AgRP-cre;Ghsr 小鼠在白天更快地消耗 HFD 餐（表现为较短的进食持续时间），但 Syn1-cre;Ghsr 小鼠在光期进食的 HFD 餐较少，并且全天进食缓慢（在两个阶段的进食持续时间都较长）。我们的发现表明，神经元 GHS-R 通过改变摄食模式来调节能量平衡，并以一种基于部位和饮食的方式差异调节摄食模式。这两种小鼠品系的独特数据还表明，在最佳进食期（对小鼠来说是暗期）缓慢进食可能有助于对抗肥胖。
