title: Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?
abstract: OBJECTIVE
  Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood.
  
  
  METHODS
  The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies.
  
  
  RESULTS
  Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes.
  
  
  CONCLUSIONS
  These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis.
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Arafat
authors.forename: P
authors.initials: P
authors.lastname: Kaczmarek
authors.forename: M
authors.initials: M
authors.lastname: Skrzypski
authors.forename: E
authors.initials: E
authors.lastname: Pruszyńska-Oszmalek
authors.forename: P
authors.initials: P
authors.lastname: Kołodziejski
authors.forename: D
authors.initials: D
authors.lastname: Szczepankiewicz
authors.forename: M
authors.initials: M
authors.lastname: Sassek
authors.forename: T
authors.initials: T
authors.lastname: Wojciechowicz
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: A F H
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: K W
authors.initials: KW
authors.lastname: Nowak
authors.forename: M Z
authors.initials: MZ
authors.lastname: Strowski
mesh_terms: D041721:3T3-L1 Cells; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D005934:Glucagon / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000097:blood*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon