Nonogaki Katsunori, Nozue Kana, Oka Yoshitomo
Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryou-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Endocrinology. 2006 Dec;147(12):5893-900. doi: 10.1210/en.2006-0418. Epub 2006 Sep 14.
The central melanocortin (MC) pathway is suggested to mediate satiety signaling downstream of serotonin (5-HT)2C receptors. 5-HT2C receptor mutant mice consume more food, which leads to late-onset obesity and impaired glucose tolerance. Ay mice with ectopic expression of the agouti peptide, which leads to a perturbation of the central MC pathway, develop obesity and diabetes, associated with low levels of plasma total ghrelin. Here, we report that 5-wk-old Ay mice consumed more food in association with decreases in levels of plasma des-acyl ghrelin, but not active ghrelin, and increases in hypothalamic 5-HT2C and 5-HT1B receptor gene expression compared with wild-type mice matched for age and body weight. These alterations were also observed in 8-wk-old obese Ay mice. Restricted feeding significantly decreased hypothalamic 5-HT2C and 5-HT1B receptor gene expression in association with a reversal of the decreases in plasma des-acyl ghrelin levels in 5-wk-old Ay mice. Moreover, restricted feeding reduced body weight, hyperinsulinemia, and hyperglycemia in association with increases in plasma des-acyl ghrelin levels in 8-wk-old obese Ay mice. Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old Ay mice, whereas the anorexic effects were attenuated in food-restricted Ay mice. These findings suggest that the agouti peptide down-regulates hypothalamic 5-HT2C and 5-HT1B receptor gene expression under restricted feeding conditions, whereas chronic hyperphagia increases the expression of these genes and decreases plasma des-acyl ghrelin levels in Ay mice.
中枢黑皮质素（MC）途径被认为可介导血清素（5-HT）2C受体下游的饱腹感信号。5-HT2C受体突变小鼠摄入更多食物，导致迟发性肥胖和糖耐量受损。携带刺鼠肽异位表达的Ay小鼠，其中枢MC途径受到干扰，会出现肥胖和糖尿病，并伴有血浆总胃饥饿素水平降低。在此，我们报告，与年龄和体重匹配的野生型小鼠相比，5周龄的Ay小鼠摄入更多食物，同时血浆去酰基胃饥饿素水平降低，但活性胃饥饿素水平未降低，且下丘脑5-HT2C和5-HT1B受体基因表达增加。在8周龄的肥胖Ay小鼠中也观察到了这些变化。限制进食显著降低了5周龄Ay小鼠下丘脑5-HT2C和5-HT1B受体基因的表达，同时血浆去酰基胃饥饿素水平的降低得到了逆转。此外，限制进食降低了8周龄肥胖Ay小鼠的体重、高胰岛素血症和高血糖，同时血浆去酰基胃饥饿素水平增加。给予间氯苯哌嗪和芬氟拉明，这两种药物均通过5-HT2C受体和/或5-HT1B受体诱导厌食效应，可抑制5周龄和8周龄Ay小鼠的食物摄入，而在食物受限的Ay小鼠中，厌食效应减弱。这些发现表明，在限制进食条件下，刺鼠肽会下调下丘脑5-HT2C和5-HT1B受体基因的表达，而长期多食会增加这些基因的表达，并降低Ay小鼠血浆去酰基胃饥饿素水平。
