title: Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion.
abstract: OBJECTIVE
  Circulating fibroblast growth factor 21 (FGF21) is an important auto- and endocrine player with beneficial metabolic effects on obesity and diabetes. In humans, thermogenic brown adipose tissue (BAT) was recently suggested as a source of FGF21 secretion during cold exposure. Here, we aim to clarify the role of UCP1 and ambient temperature in the regulation of FGF21 in mice.
  
  
  METHODS
  Wildtype (WT) and UCP1-knockout (UCP1 KO) mice, the latter being devoid of BAT-derived non-shivering thermogenesis, were exposed to different housing temperatures. Plasma metabolites and FGF21 levels were determined, gene expression was analyzed by qPCR, and tissue histology was performed with adipose tissue.
  
  
  RESULTS
  At thermoneutrality, FGF21 gene expression and serum levels were not different between WT and UCP1 KO mice. Cold exposure led to highly increased FGF21 serum levels in UCP1 KO mice, which were reflected in increased FGF21 gene expression in adipose tissues but not in liver and skeletal muscle. Ex vivo secretion assays revealed FGF21 release only from BAT, progressively increasing with decreasing ambient temperatures. In association with increased FGF21 serum levels in the UCP1 KO mouse, typical FGF21-related serum metabolites and inguinal white adipose tissue morphology and thermogenic gene expression were altered.
  
  
  CONCLUSIONS
  Here we show that the genetic ablation of UCP1 increases FGF21 gene expression in adipose tissue. The removal of adaptive nonshivering thermogenesis renders BAT a significant source of endogenous FGF21 under thermal stress. Thus, the thermogenic competence of BAT is not a requirement for FGF21 secretion. Notably, high endogenous FGF21 levels in UCP1-deficient models and subjects may confound pharmacological FGF21 treatments.
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Keipert
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kutschke
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamp
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Brachthäuser
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany ; Department of Animal Physiology, Philipps-Universität, 35043 Marburg, Germany.
authors.forename: Carola W
authors.initials: CW
authors.lastname: Meyer
authors.affiliation: Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, 53105 Bonn, Germany ; Department of Animal Physiology, Philipps-Universität, 35043 Marburg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Oelkrug
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, 47405 IN, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany ; Department of Animal Physiology, Philipps-Universität, 35043 Marburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
keywords: BAT; FGF21; Obesity; Thermogenesis; UCP1; iWAT