title: Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients.
abstract: 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 β-Klotho, in liver and adipose tissues.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  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 β-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity.
authors.affiliation: 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.
authors.forename: J M
authors.initials: JM
authors.lastname: Gallego-Escuredo
authors.affiliation: 1] CIBER Fisiopatología de la Obesidad y Nutrición, Nutrición, Spain [2] Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Gómez-Ambrosi
authors.affiliation: 1] CIBER Fisiopatología de la Obesidad y Nutrición, Nutrición, Spain [2] Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Catalan
authors.affiliation: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Domingo
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Giralt
authors.affiliation: 1] CIBER Fisiopatología de la Obesidad y Nutrición, Nutrición, Spain [2] Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Frühbeck
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Villarroya
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005947:Glucose; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D013030:Spain; D013851:Thinness / Q000378:metabolism*
chemical_list: C117476:FGF19 protein, human; C538995:KLB protein, human; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins; D005947:Glucose