Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients
Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients
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DOI：
10.1038/ijo.2014.76
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发表时间：
2015-01-01
影响因子：
4.9
通讯作者：
Villarroya, F.
中科院分区：
文献类型：
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作者：
Gallego-Escuredo, J. M.;Gomez-Ambrosi, J.;Villarroya, F.
目的：成纤维细胞生长因子（FGF）-21，可能还有FGF 19，在啮齿类动物中对2型糖尿病（T2 DM）和肥胖具有保护作用。我们研究了不同程度的血糖稳态异常的肥胖患者的FGF 21和FGF 19的循环水平，并测定了肝脏和脂肪组织中FGF受体（FGFR 1 -4）和辅助受体β-Klotho的基因表达。（49%男性，中位体重指数（BMI）：40.5 kgm（-2），四分位距：34.7-46.2）。在肥胖患者中，36例血糖正常，15例糖耐量受损，10例患有T2 DM。分析了来自肥胖患者和对照组的肝脏、内脏和皮下脂肪活检。采用酶联免疫吸附法测定组织中FGF 19和FGF 21的水平，采用逆转录聚合酶链反应和免疫印迹法测定组织中mRNA和蛋白质的水平。结果：肥胖患者血清中FGF 21水平明显高于对照组（P < 0.001），而FGF 19水平则下降（Po0.001）。FGF 21水平与胰岛素抵抗（P = 0.0002，r = 0.37）和胰岛素（P = 0.001，r = 0.32）的稳态模型评估呈正相关，而FGF 19水平呈负相关（分别为P = 0.007，r = -0.27; P = 0.003，r = -0.28）。校正BMI后，FGF 21和FGF 19水平与血糖稳态异常指标的相关性不显著。在肥胖患者中，肝脏FGF 21的表达增加。（P = 0.04）。内脏脂肪中的β-Klotho转录水平（P = 0.002）和皮下注射β-Klotho蛋白水平（P = 0.03）和内脏脂肪（P = 0.04）在肥胖患者中显著降低，而肝脏中β-Klotho结论：肥胖的特征是FGF 19（减少）和FGF 21（增加）水平的相互改变。虽然在糖尿病肥胖患者中恶化，但肥胖本身似乎是FGF 21和FGF 19水平异常的主要决定因素。脂肪和肝脏中β-Klotho表达的相反变化表明肥胖症对内分泌FGF的反应性存在潜在的组织特异性改变。
OBJECTIVE: Fibroblast growth factor (FGF)-21, and possibly FGF19, protect against type 2 diabetes mellitus (T2DM) and obesity in rodents. We investigated the circulating levels of FGF21 and FGF19 in obese patients with varying degrees of abnormal glucose homeostasis, and we determined gene expression for FGF receptors (FGFR1-4) and the co-receptor beta-Klotho, in liver and adipose tissues.SUBJECTS AND METHODS: We analyzed 35 lean healthy (71% men) and 61 obese patients (49% men, median body mass index (BMI): 40.5 kgm(-2), interquartile range: 34.7-46.2). Among obese patients, 36 were normoglycemic, 15 showed impaired glucose tolerance and 10 had T2DM. Biopsies from liver and visceral and subcutaneous fat from a subset of obese patients and controls were analyzed. FGF19 and FGF21 levels were measured using enzyme-linked immunosorbent assay, and tissue mRNA and protein levels by reverse transcription-polymerase chain reaction and immunoblotting.RESULTS: FGF21 serum levels were significantly increased in obese patients compared with controls (P < 0.001), whereas FGF19 levels were decreased (Po0.001). FGF21 levels were positively correlated with homeostasis model assessment of insulin resistance (P = 0.0002, r = 0.37) and insulin (P = 0.001, r = 0.32), whereas FGF19 levels were negatively correlated (P = 0.007, r = -0.27; P = 0.003, r = -0.28; respectively). After adjusting for BMI, the correlations of FGF21 and FGF19 levels with indicators of abnormal glucose homeostasis were not significant. In obese patients, the hepatic expression of FGF21 was increased. (P = 0.04). beta-Klotho transcript levels in visceral fat (P = 0.002) and beta-Klotho protein levels in subcutaneous (P = 0.03) and visceral fat (P = 0.04) were significantly reduced in obese patients, whereas hepatic levels for beta-Klotho (P = 0.03), FGFR1 (P = 0.04) and FGFR3 (P = 0.001) transcripts were significantly increased.CONCLUSIONS: Obesity is characterized by reciprocal alterations in FGF19 (decrease) and FGF21 (increase) levels. Although worsened in diabetic obese patients, obesity itself appears as the predominant determinant of the abnormalities in FGF21 and FGF19 levels. Opposite changes in beta-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity.