title: FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice.
abstract: OBJECTIVE
  Ketogenic diets (KDs) have increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. The metabolic benefits of KDs are regularly ascribed to enhanced hepatic secretion of fibroblast growth factor 21 (FGF21) and its systemic effects on fatty-acid oxidation, energy expenditure (EE) and body weight. Ambiguous data from Fgf21-knockout animal strains and low FGF21 concentrations reported in humans with ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating the therapeutic benefits of KDs on metabolism and cancer.
  
  
  METHODS
  We established a dietary model of increased vs decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted of protein or enriched with protein. We furthermore used wild-type and Fgf21-knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumour growth after transplantation of Lewis lung carcinoma cells.
  
  
  RESULTS
  Hepatic and circulating, but not adipose tissue, FGF21 levels were profoundly increased by protein starvation, independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycaemia upon protein and carbohydrate starvation and is therefore not needed for the effects of KDs on EE. Furthermore, the tumour-suppressing effects of KDs were independent of FGF21 and, rather, driven by concomitant protein and carbohydrate starvation.
  
  
  CONCLUSIONS
  Our data indicate that the multiple systemic effects of KD exposure in mice, previously ascribed to increased FGF21 secretion, are rather a consequence of protein malnutrition.
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Zani
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine-Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Neff
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kotzbeck
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Suma
authors.initials: S
authors.lastname: Yalamanchilli
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Azad
authors.affiliation: LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Lehti
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Paulo J F
authors.initials: PJ
authors.lastname: Martins
authors.affiliation: Division of Molecular Pharmacology, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Research Unit NeuroBiology of Diabetes, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.affiliation: Department of Surgery, University of Michigan, North Campus Research Center, 2800 Plymouth Road, Ann Arbor, MI, 48109-2800, USA. seeleyrj@umich.edu.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D055423:Diet, Ketogenic; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D007662:Ketosis / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000178:diet therapy / Q000235:genetics* / Q000378:metabolism; D011488:Protein Deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose
keywords: Energy expenditure; Fibroblast growth factor 21; Glucose homeostasis; Ketogenic diets; Protein starvation; Tumour suppression