Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, The Netherlands.
Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E477-88. doi: 10.1152/ajpendo.00154.2009. Epub 2009 Nov 24.
Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch(-/-) rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch(-/-) rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.
出生后发育和青春期是身体快速成熟的时期，需要大量的能量。下丘脑神经肽黑皮质素原（Pmch）调节营养摄入和能量平衡，但潜在的机制尚不完全清楚。在这里，我们使用一种新的大鼠基因敲除模型，其中 Pmch 前体已被失活，以更详细地研究缺失 MCH 对能量调节的影响。Pmch(-/-) 大鼠体型消瘦、食欲减退、骨质疏松，尽管 pmch(-/-) 大鼠的内分泌参数发生了变化，但内分泌动力学正常，这表明它们适应了新的稳态水平，而不是代谢机制受到干扰。详细的体重增长和摄食行为分析表明，Pmch 在大鼠早期发育和青春期（即出生后 8 周内）表达尤为重要。Pmch 的缺失导致体重设定点降低 20%，而这一设定点仅在这一时期确定，成年后保持不变。尽管最终体重取决于饮食，但在本研究中测试的所有饮食对 Pmch 缺乏的影响相似。Pmch 的缺失影响了幼鼠和成年鼠的能量消耗，尽管这些影响似乎是由于观察到的食欲减退所致。我们的研究结果表明 Pmch 在早期发育过程中对能量平衡的确定起着重要作用，并表明 MCH 受体 1 系统是治疗儿童肥胖症的一个合理靶点，而肥胖症目前是第一世界国家的一个主要健康问题。
