Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance.
Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance.
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DOI：
10.2337/db10-0074
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发表时间：
2010-12
期刊：
影响因子：
7.7
通讯作者：
Kieffer TJ
中科院分区：
文献类型：
--
作者：
Huynh FK;Levi J;Denroche HC;Gray SL;Voshol PJ;Neumann UH;Speck M;Chua SC;Covey SD;Kieffer TJ
肝脏在整合和控制葡萄糖代谢方面起着至关重要的作用。因此，肝脏接收来自其他组织的有关身体营养状况的信号并做出反应非常重要。瘦素由脂肪组织产生和分泌，是一种将脂肪库状态信息传递到身体其他部位的激素。瘦素对葡萄糖代谢具有深远的影响，因此我们试图确定瘦素是否可以部分通过肝脏发挥这种作用。为了探索这种可能性，我们使用 Cre-lox 方法培育了破坏肝脏瘦素信号传导的小鼠，然后研究了这些动物的葡萄糖代谢的各个方面。在轻度禁食或随机进食状态下，肝脏瘦素信号传导的丧失不会改变体重、身体成分或血糖水平。然而，肝脏瘦素信号被消除的小鼠肝脏中的脂质积累增加。此外，随着雄性小鼠衰老或喂食高脂肪饮食，肝脏瘦素信号传导的丧失可以保护小鼠免受葡萄糖不耐受。此外，小鼠的肝脏胰岛素敏感性增加，并且葡萄糖刺激的血浆胰岛素水平有增加的趋势。与胰岛素敏感性增加一致，肝脏瘦素信号传导被消除的小鼠肝脏中胰岛素刺激的 Akt 磷酸化增加。这些数据表明，与瘦素作用完全缺乏会导致葡萄糖稳态受损不同，仅肝脏中瘦素作用的破坏会增加肝脏胰岛素敏感性，并防止与年龄和饮食相关的葡萄糖不耐受。因此，瘦素似乎充当肝脏中胰岛素作用的负调节剂。
The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver. To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals. The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver. These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.