Singh Amandeep, Wirtz Martin, Parker Nadeene, Hogan Matthew, Strahler John, Michailidis George, Schmidt Sarah, Vidal-Puig Antonio, Diano Sabrina, Andrews Philip, Brand Martin D, Friedman Jeffrey
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13100-5. doi: 10.1073/pnas.0903723106. Epub 2009 Jul 21.
Leptin reduces body weight in ob/ob mice by decreasing food intake and increasing energy expenditure; however, the mechanisms by which it does the latter are not known. Here we report that 30% of the weight loss induced by leptin treatment of ob/ob mice is due to changes in energy expenditure. In assessing leptin's effects on specific tissues, we found that hepatic basal metabolic rate was paradoxically decreased 1.7-fold with leptin treatment, which was the result of a 1.6-fold reduction in mitochondrial volume density and altered substrate oxidation kinetics. The altered kinetics were associated with a decrease in protein levels of 2 mitochondrial respiratory chain components--cytochrome c oxidase subunit VIa and cytochrome c oxidase subunit IV. In addition to reduced hepatic metabolism, there was reduced long chain fatty acid production and a 2.5-fold increase in hepatic lipid export, both of which explain the reduced steatosis in leptin-treated animals. These data help clarify the role of the liver in leptin-mediated weight loss and define the mechanisms by which leptin alters hepatic metabolism and corrects steatosis.
瘦素通过减少食物摄入和增加能量消耗来降低ob/ob小鼠的体重；然而，其增加能量消耗的机制尚不清楚。在此我们报告，瘦素治疗ob/ob小鼠所诱导的体重减轻中有30%是由于能量消耗的变化。在评估瘦素对特定组织的影响时，我们发现，瘦素治疗使肝脏基础代谢率反常地降低了1.7倍，这是线粒体体积密度降低1.6倍以及底物氧化动力学改变的结果。动力学改变与两种线粒体呼吸链成分——细胞色素c氧化酶亚基VIa和细胞色素c氧化酶亚基IV的蛋白质水平降低有关。除了肝脏代谢减少外，长链脂肪酸生成减少，肝脏脂质输出增加2.5倍，这两者都解释了瘦素治疗动物脂肪变性减轻的原因。这些数据有助于阐明肝脏在瘦素介导的体重减轻中的作用，并确定瘦素改变肝脏代谢和纠正脂肪变性的机制。
