FGF21 Is Increased by Inflammatory Stimuli and Protects Leptin-Deficient ob/ob Mice from the Toxicity of Sepsis
FGF21 Is Increased by Inflammatory Stimuli and Protects Leptin-Deficient ob/ob Mice from the Toxicity of Sepsis
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DOI：
10.1210/en.2011-1496
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发表时间：
2012-06-01
期刊：
影响因子：
4.8
通讯作者：
Kharitonenkov, Alexei
中科院分区：
文献类型：
--
作者：
Feingold, Kenneth R.;Grunfeld, Carl;Kharitonenkov, Alexei
急性期反应（APR）引起脂质和碳水化合物代谢的显著改变，包括血浆酮水平降低。成纤维细胞生长因子21（FGF 21）是最近发现的调节脂质和葡萄糖代谢并刺激生酮的激素。在这里，我们证明，脂多糖（LPS），酵母多糖，和turtophan，诱导APR，增加血清FGF 21水平的2倍。虽然LPS、酵母聚糖和姜黄素降低了肝脏中FGF 21的表达，但它们增加了脂肪组织和肌肉中FGF 21的表达，这表明肝外组织导致了血清中FGF 21的增加。LPS给药后，FGF 21-/-小鼠血浆酮水平的特征性降低加重，但这不是由于肝脏中肉毒碱棕榈酰转移酶1 α或羟甲基戊二酰辅酶A合酶2表达的差异，因为LPS诱导FGF 21-/-和对照小鼠中这些基因表达的相似降低。然而，在FGF 21-/-小鼠中，LPS增加血浆游离脂肪酸水平的能力减弱。未能增加血浆游离脂肪酸可能导致血浆酮水平显著降低，因为脂肪酸从脂肪组织转运至肝脏为酮生成提供了底物。外源性FGF 21治疗可减少瘦素缺陷型ob/ob小鼠和对照组小鼠在LPS给药后死亡的动物数量和死亡速度。FGF 21还保护盲肠结扎和穿刺诱导的脓毒症的毒性作用。因此，FGF 21是一种保护动物免受LPS和脓毒症毒性作用的阳性APR蛋白。（内分泌学153：2689-2700，2012）
The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21 -/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1 alpha or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21 -/- and control mice. However, in FGF21 -/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis. (Endocrinology 153: 2689-2700, 2012)