Lim Maria A, Bence Kendra K, Sandesara Ishani, Andreux Pénélope, Auwerx Johan, Ishibashi Jeff, Seale Patrick, Kalb Robert G
Division of Neurology, Department of Pediatrics, Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA, Neuroscience Graduate Group.
Neuroscience Graduate Group, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2014 Sep 15;23(18):4995-5008. doi: 10.1093/hmg/ddu214. Epub 2014 May 15.
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron disease.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，会导致运动神经元死亡。ALS患者和家族性ALS小鼠模型表现出机体水平的代谢功能障碍，包括尽管瘦体重下降但能量消耗增加。能量稳态异常与运动神经元疾病的病理生理相关性仍不清楚。瘦素是一种由脂肪细胞分泌的激素，可调节全身能量消耗。在此，我们报告将突变型超氧化物歧化酶1（SOD1）小鼠置于瘦素缺乏的背景下可改善能量稳态并减缓疾病进展。瘦素缺乏的突变型SOD1小鼠体重和脂肪量增加，能量消耗减少。这些观察结果与生存率提高、力量改善和运动神经元损失减少相一致。这些结果表明，改变突变型SOD1小鼠的全身能量代谢可以减轻疾病进展。我们提出，增加脂肪量和减少能量消耗的操作在运动神经元疾病的情况下将是有益的。
