title: Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage.
abstract: OBJECTIVE
  Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates glucose and lipid metabolism in rodents. The effects of obesity and fatty liver on circulating FGF-21 levels have been described mainly in adults. Herein, we measured plasma FGF-21 levels in lean and obese adolescents with low and high hepatic fat content (HFF% <5.5% and HFF% ≥ 5.5%, respectively) and explored their relationship with hepatic fat content, measures of hepatic apoptosis, and insulin sensitivity.
  
  
  METHODS
  A total of 217 lean and obese adolescents with both low and high HFF% (lean = 31; obese low HFF% = 107; and obese high HFF% = 79) underwent an oral glucose tolerance test, a fast gradient magnetic resonance imaging to measure the %HFF and abdominal fat distribution. Cytokeratin 18 levels were measured as a biomarker of liver apoptosis. A subset of adolescents underwent a 2-step hyperinsulinemic-euglycemic clamp, and a liver biopsy (N = 14), to assess insulin sensitivity and steatohepatitis, respectively.
  
  
  RESULTS
  Compared to controls, FGF-21 levels were higher in obese youth, especially in those with high HFF (P < .001). FGF-21 significantly correlated with adiposity indexes (P < .001), visceral fat (r² = 0.240, P < .001), hepatic fat content (r² = 0.278, P < .001), cytokeratin 18 (r² = 0.217, P < .001), and alanine aminotransferase (r² = .164, P < .001). In subjects with steatoheaptitis, FGF-21 levels significantly correlated with the nonalcoholic fatty liver disease activity score (r² = 0.27, P = .04). Stepwise regression analysis indicated that these relationships are independent of body mass index, visceral fat, and insulin sensitivity. An inverse correlation was documented with insulin, hepatic resistance indexes, and adipose resistance indexes, which disappeared after adjusting for hepatic fat content.
  
  
  CONCLUSIONS
  Plasma FGF-21 levels are increased in obese adolescents, particularly in those with fatty liver. FGF-21 concentrations significantly and independently correlate with hepatic fat content and markers of hepatic apoptosis in obese youths.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Giannini
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.forename: Bridget
authors.initials: B
authors.lastname: Pierpont
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
mesh_terms: D050154:Adiposity; D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D048550:Hepatic Insufficiency / Q000209:etiology*; D006801:Humans; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D053538:Keratin-18 / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008137:Longitudinal Studies; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000097:blood* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; C488421:KRT18 protein, human; D053538:Keratin-18; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000410:Alanine Transaminase