Department of Clinical Research, Section of Molecular Diabetes and Metabolism, University of Southern Denmark, Odense, Denmark.
Department of Molecular Medicine, Section of Molecular Diabetes and Metabolism, University of Southern Denmark, Odense, Denmark.
Diabetologia. 2017 Oct;60(10):2042-2051. doi: 10.1007/s00125-017-4373-5. Epub 2017 Jul 18.
AIMS/HYPOTHESIS: Pharmacological doses of FGF21 improve glucose tolerance, lipid metabolism and energy expenditure in rodents. Induced expression and secretion of FGF21 from muscle may increase browning of white adipose tissue (WAT) in a myokine-like manner. Recent studies have reported that insulin and exercise increase FGF21 in plasma. Obesity and type 2 diabetes are potentially FGF21-resistant states, but to what extent FGF21 responses to insulin and exercise training are preserved, and whether FGF21, its receptors and target genes are altered, remains to be established.
The effects of insulin during euglycaemic-hyperinsulinaemic clamps and 10 week endurance training on serum FGF21 were examined in individuals with type 2 diabetes and in glucose tolerant overweight/obese and lean individuals. Gene expression of FGF21, its receptors and target genes in muscle and WAT biopsies was evaluated by quantitative real-time PCR (qPCR).
Insulin increased serum and muscle FGF21 independent of overweight/obesity or type 2 diabetes, and there were no effects associated with exercise training. The insulin-induced increases in serum FGF21 and muscle FGF21 expression correlated tightly (p < 0.001). In WAT, overweight/obesity with and without type 2 diabetes led to reduced expression of KLB, but increased FGFR1c expression. However, the expression of most FGF21 target genes was unaltered except for reduced CIDEA expression in individuals with type 2 diabetes.
CONCLUSIONS/INTERPRETATION: Insulin-induced expression of muscle FGF21 correlates strongly with a rise in serum FGF21, and this response appears intact in overweight/obesity and type 2 diabetes. FGF21 resistance may involve reduced KLB expression in WAT. However, increased FGFR1c expression or other mechanisms seem to ensure adequate expression of most FGF21 target genes in WAT.
目的/假设：成纤维细胞生长因子 21（FGF21）的药理剂量可改善啮齿动物的葡萄糖耐量、脂代谢和能量消耗。肌肉中 FGF21 的诱导表达和分泌可能以肌因子样方式增加白色脂肪组织（WAT）的褐色化。最近的研究报道，胰岛素和运动可增加血浆中的 FGF21。肥胖和 2 型糖尿病可能是 FGF21 抵抗状态，但胰岛素和运动训练对 FGF21 的反应在多大程度上得到保留，以及 FGF21、其受体和靶基因是否发生改变，仍有待确定。
在 2 型糖尿病患者以及葡萄糖耐量超重/肥胖和瘦个体中，检查了在正常血糖高胰岛素钳夹和 10 周耐力训练期间胰岛素对血清 FGF21 的影响。通过实时定量 PCR（qPCR）评估肌肉和 WAT 活检中 FGF21、其受体和靶基因的基因表达。
胰岛素增加了血清和肌肉 FGF21 的表达，这与超重/肥胖或 2 型糖尿病无关，也与运动训练无关。血清 FGF21 和肌肉 FGF21 表达的胰岛素诱导增加密切相关（p<0.001）。在 WAT 中，超重/肥胖伴或不伴 2 型糖尿病导致 KLB 表达降低，但 FGFR1c 表达增加。然而，大多数 FGF21 靶基因的表达没有改变，除了 2 型糖尿病患者的 CIDEA 表达降低。
结论/解释：胰岛素诱导的肌肉 FGF21 表达与血清 FGF21 的升高密切相关，在超重/肥胖和 2 型糖尿病中，这种反应似乎是完整的。FGF21 抵抗可能涉及 WAT 中 KLB 表达降低。然而，FGFR1c 表达的增加或其他机制似乎确保了 WAT 中大多数 FGF21 靶基因的充分表达。
