Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Diabetes. 2010 Dec;59(12):3032-40. doi: 10.2337/db10-0074. Epub 2010 Sep 28.
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.
肝脏在整合和控制糖代谢方面起着关键作用。因此,肝脏接收和响应来自其他组织关于身体营养状况的信号非常重要。瘦素由脂肪组织产生和分泌,是一种向身体其他部位传递脂肪储存状态信息的激素。瘦素对糖代谢有深远的影响,因此我们试图确定瘦素是否可以通过肝脏部分发挥这种作用。
为了探索这种可能性,我们使用 Cre-lox 方法创建了肝脏瘦素信号中断的小鼠,并研究了这些动物的糖代谢的各个方面。
肝脏瘦素信号的缺失不会改变轻度禁食或随机喂养状态下的体重、身体成分或血糖水平。然而,肝脏瘦素信号缺失的小鼠肝脏脂质积累增加。此外,随着雄性小鼠年龄的增长或喂食高脂肪饮食,肝脏瘦素信号的缺失使小鼠免受葡萄糖不耐受的影响。此外,这些小鼠表现出更高的肝脏胰岛素敏感性和增加的葡萄糖刺激的血浆胰岛素水平的趋势。与增加的胰岛素敏感性一致,肝脏瘦素信号缺失的小鼠肝脏胰岛素刺激的 Akt 磷酸化增加。
这些数据表明,与瘦素作用完全缺失导致糖稳态受损不同,肝脏中瘦素作用的破坏仅增加肝脏胰岛素敏感性并预防与年龄和饮食相关的葡萄糖不耐受。因此,瘦素似乎在肝脏中作为胰岛素作用的负调节剂发挥作用。