Interplay between FGF21 and insulin action in the liver regulates metabolism
Interplay between FGF21 and insulin action in the liver regulates metabolism
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DOI：
10.1172/jci67353
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
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作者：
Emanuelli, Brice;Vienberg, Sara G.;Kahn, C. Ronald
激素FGF21调节碳水化合物和脂肪的动态平衡以及体重，增加FGF21可以改善与肥胖和糖尿病相关的代谢异常。FGF21被认为作用于其靶组织，包括肝脏和脂肪组织，以提高胰岛素敏感性和减少肥胖。在这里，我们使用选择性肝脏IR失活(LIRKO)的小鼠来确定肝脏中的胰岛素敏化是否介导了FGF21的代谢作用。值得注意的是，在接受FGF21治疗后，LIRKO小鼠的高血糖完全恢复正常，尽管FGF21不会减少这些动物的糖异生。血糖的改善部分是由于棕色脂肪中葡萄糖摄取的增加，白色脂肪的褐化，以及整体能量消耗的增加。即使在移除主要的肩胛间棕色脂肪垫后，这些效果仍被保留下来。与其保留的降血糖作用相反，在LIRKO小鼠中，FGF21降低循环胆固醇和肝甘油三酯以及调节涉及胆固醇和脂肪代谢的关键基因的作用被破坏。因此，FGF21通过激活棕色脂肪和褐化白色脂肪来增加能量代谢，从而独立于肝脏中的胰岛素作用来纠正糖尿病小鼠的高血糖，但FGF21需要完整的肝脏胰岛素作用来控制肝脏的脂肪代谢。
The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism.