Hohmann J G, Teklemichael D N, Weinshenker D, Wynick D, Clifton D K, Steiner R A
Neurobiology and Behavior, Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Mol Cell Biol. 2004 Apr;24(7):2978-85. doi: 10.1128/MCB.24.7.2978-2985.2004.
Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL(-/-)/NPY(-/-)). We found that male GAL(-/-)/NPY(-/-) mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL(-/-)/NPY(-/-) mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL(-/-)/NPY(-/-) mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY(-/-) mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL(-/-)/NPY(-/-) double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range.
神经肽Y（NPY）和甘丙肽都与体重调节有关，但敲除这两种分子中任何一种的小鼠都没有明显的代谢表型。为了研究甘丙肽和NPY是否可能相互补偿，我们培育了同时缺乏这两种神经肽的突变体（GAL(-/-)/NPY(-/-)）。我们发现，雄性GAL(-/-)/NPY(-/-)小鼠的食量明显增加，体重比野生型（WT）对照重得多（30%）。GAL(-/-)/NPY(-/-)小鼠对高脂饮食的反应是比WT小鼠增重更多，并且在饮食改变后无法正常调节体重。GAL(-/-)/NPY(-/-)小鼠的瘦素、胰岛素和葡萄糖水平升高，在长期瘦素治疗期间，它们比WT小鼠体重减轻更多。NPY(-/-)小鼠下丘脑的甘丙肽mRNA增加，这为单突变体中的代偿性调节提供了证据。在GAL(-/-)/NPY(-/-)双敲除小鼠中观察到的能量平衡紊乱在这两种分子的单敲除表型中并未出现。这种意外的肥胖表型可能是由于通常将体重维持在稳态范围内的瘦素和胰岛素系统失调所致。
