Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice
Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice
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DOI：
10.1210/en.2014-1292
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发表时间：
2014-11-01
期刊：
影响因子：
4.8
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
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作者：
Chen, Weiqin;Zhou, Hongyi;Chan, Lawrence
Bscl2(-/-)小鼠概括了Berardinelli-Seip先天性脂肪营养不良2型(BSCL2)患者的许多主要代谢表现，包括脂肪营养不良、肝肿大、肝脏脂肪变性和胰岛素抵抗。Bscl2(-/-)小鼠肝脏脂肪变性和胰岛素抵抗的机制尚不清楚。为了解决这个问题，我们对Bscl2(-/-)和野生型小鼠进行了隔夜(16-h)禁食后的高胰岛素-正常血糖钳夹试验，发现Bscl2(-/-)实际上显示出肝脏胰岛素敏感性增加。有趣的是，Bscl2(-/-)小鼠在短期禁食(4小时)后，肝脏损伤了急性胰岛素信号，这一缺陷在禁食16小时后消失。值得注意的是，Bscl2(-/-)小鼠的空腹依赖的肝脏胰岛素信号与肝脏二酰甘油和神经酰胺的含量无关，但可能部分归因于肝脏胰岛素信号受体和底物的表达。同时，喂养或短期禁食的Bscl2(-/-)小鼠新生脂肪生成增加和β-氧化减少导致严重的肝脏脂肪变性，而长时间禁食显著影响Bscl2(-/-)小鼠的肝脏脂肪堆积和代谢。此外，肝脏特异性Bscl2失活的小鼠即使在高脂饮食下也没有表现出肝脏脂肪变性，这表明Bscl2在调节肝脏脂质稳态方面没有发挥细胞自主作用。总体而言，我们的结果为肝脏对禁食反应的代谢适应提供了新的见解，并在人类BSCL2小鼠模型中发现了一种新的依赖于禁食的肝脏胰岛素信号调节。
Bscl2(-/-) mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2(-/-) mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2(-/-) and wild-type mice after an overnight (16-h) fast, and found that Bscl2(-/-) actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2(-/-) mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-hour fast. Notably, fasting-dependent hepatic insulin signaling in Bscl2(-/-) mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased beta-oxidation led to severe hepatic steatosis in fed or short-fasted Bscl2(-/-) mice whereas liver lipid accumulation and metabolism in Bscl2(-/-) mice was markedly affected by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high-fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.