Gallego-Escuredo J M, Gómez-Ambrosi J, Catalan V, Domingo P, Giralt M, Frühbeck G, Villarroya F
1] Department of Biochemistry and Molecular Biology and Institute of Biomedicina, University of Barcelona, Barcelona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición, Nutrición, Spain.
1] CIBER Fisiopatología de la Obesidad y Nutrición, Nutrición, Spain [2] Clínica Universidad de Navarra, Pamplona, Spain.
Int J Obes (Lond). 2015 Jan;39(1):121-9. doi: 10.1038/ijo.2014.76. Epub 2014 May 12.
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 β-Klotho, in liver and adipose tissues.
We analyzed 35 lean healthy (71% men) and 61 obese patients (49% men, median body mass index (BMI): 40.5 kg m(-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.
FGF21 serum levels were significantly increased in obese patients compared with controls (P<0.001), whereas FGF19 levels were decreased (P < 0.001). 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). β-Klotho transcript levels in visceral fat (P = 0.002) and β-Klotho protein levels in subcutaneous (P = 0.03) and visceral fat (P = 0.04) were significantly reduced in obese patients, whereas hepatic levels for β-Klotho (P = 0.03), FGFR1 (P = 0.04) and FGFR3 (P = 0.001) transcripts were significantly increased.
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 β-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity.
成纤维细胞生长因子（FGF）-21以及可能的FGF19可预防啮齿动物的2型糖尿病（T2DM）和肥胖。我们研究了不同程度葡萄糖稳态异常的肥胖患者中FGF21和FGF19的循环水平，并测定了肝脏和脂肪组织中FGF受体（FGFR1 - 4）和共受体β-klotho的基因表达。
我们分析了35名健康瘦人（71%为男性）和61名肥胖患者（49%为男性，体重指数（BMI）中位数：40.5 kg/m²，四分位间距：34.7 - 46.2）。在肥胖患者中，36人血糖正常，15人糖耐量受损，10人患有T2DM。对一部分肥胖患者和对照的肝脏、内脏脂肪和皮下脂肪活检样本进行了分析。使用酶联免疫吸附测定法测量FGF19和FGF21水平，通过逆转录 - 聚合酶链反应和免疫印迹法测定组织mRNA和蛋白质水平。
与对照组相比，肥胖患者的FGF21血清水平显著升高（P<0.001），而FGF19水平降低（P<0.001）。FGF21水平与胰岛素抵抗的稳态模型评估呈正相关（P = 0.0002，r = 0.37）和胰岛素呈正相关（P = 0.001，r = 0.32），而FGF19水平呈负相关（分别为P = 0.007，r = -0.27；P = 0.003，r = -0.28）。在调整BMI后，FGF21和FGF19水平与葡萄糖稳态异常指标的相关性不显著。在肥胖患者中，FGF21的肝脏表达增加（P = 0.04）。肥胖患者内脏脂肪中的β-klotho转录水平（P = 0.002）以及皮下（P = 0.03）和内脏脂肪中的β-klotho蛋白水平（P = 0.04）显著降低，而肝脏中β-klotho（P = 0.03）、FGFR1（P = 0.04）和FGFR3（P = 0.001）转录水平显著升高。
肥胖的特征是FGF19（降低）和FGF21（升高）水平的相互改变。尽管在糖尿病肥胖患者中情况更糟，但肥胖本身似乎是FGF21和FGF19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中对内分泌FGFs反应性存在潜在的组织特异性改变。
