title: Fibroblast growth factor 21 is elevated in metabolically unhealthy obesity and affects lipid deposition, adipogenesis, and adipokine secretion of human abdominal subcutaneous adipocytes.
abstract: OBJECTIVE
  Serum concentrations of the hepatokine fibroblast growth factor (FGF) 21 are elevated in obesity, type-2 diabetes, and the metabolic syndrome. We asked whether FGF21 levels differ between subjects with metabolically healthy vs. unhealthy obesity (MHO vs. MUHO), opening the possibility that FGF21 is a cross-talker between liver and adipose tissue in MUHO. Furthermore, we studied the effects of chronic FGF21 treatment on adipocyte differentiation, lipid storage, and adipokine secretion.
  
  
  METHODS
  In 20 morbidly obese donors of abdominal subcutaneous fat biopsies discordant for their whole-body insulin sensitivity (hereby classified as MHO or MUHO subjects), serum FGF21 was quantified. The impact of chronic FGF21 treatment on differentiation, lipid accumulation, and adipokine release was assessed in isolated preadipocytes differentiated in vitro.
  
  
  RESULTS
  Serum FGF21 concentrations were more than two-fold higher in MUHO as compared to MHO subjects (457 ± 378 vs. 211 ± 123 pg/mL; p < 0.05). FGF21 treatment of human preadipocytes for the entire differentiation period was modestly lipogenic (+15%; p < 0.05), reduced the expression of key adipogenic transcription factors (PPARG and CEBPA, -15% and -40%, respectively; p < 0.01 both), reduced adiponectin expression (-20%; p < 0.05), markedly reduced adiponectin release (-60%; p < 0.01), and substantially increased leptin (+60%; p < 0.01) and interleukin-6 (+50%; p < 0.001) release.
  
  
  CONCLUSIONS
  The hepatokine FGF21 exerts weak lipogenic and anti-adipogenic actions and marked adiponectin-suppressive and leptin and interleukin-6 release-promoting effects in human differentiating preadipocytes. Together with the higher serum concentrations in MUHO subjects, our findings reveal FGF21 as a circulating factor promoting the development of metabolically unhealthy adipocytes.
authors.affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Berti
authors.affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany.
authors.forename: Marty
authors.initials: M
authors.lastname: Zdichavsky
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meile
authors.affiliation: German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Böhm
authors.affiliation: German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Chair for Experimental Genetics, Technical University Munich, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Straße 3, D-72076 Tübingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Institute of Experimental Genetics, Helmholtz Centre Munich GmbH, German Research Centre for Environmental Health, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Chair for Experimental Genetics, Technical University Munich, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: German Centre for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany ; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
keywords: AMPK, AMP-activated protein kinase; Adipokine; Adiponectin; BMI, body mass index; C/EBP-α, CCAAT/enhancer-binding protein-α; CIDEA, cell death-inducing DNA fragmentation factor-like effector a; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGF21; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Hepatokine; IL-6, interleukin-6; MHO, metabolically healthy obesity; MUHO, metabolically unhealthy obesity; PGC-1α, PPAR-γ coactivator-1α; PPAR-γ, peroxisome proliferator-activated receptor-γ; Secretome; Type-2 diabetes; UCP-1, uncoupling protein-1; hasc, human abdominal subcutaneous; qPCR, quantitative polymerase chain reaction; rh, recombinant human