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Diabetologia
Published in: Diabetologia 10/2015

01-10-2015 | Article

FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice

Authors: Kerstin Stemmer, Fabio Zani, Kirk M. Habegger, Christina Neff, Petra Kotzbeck, Michaela Bauer, Suma Yalamanchilli, Ali Azad, Maarit Lehti, Paulo J. F. Martins, Timo D. Müller, Paul T. Pfluger, Randy J. Seeley

Published in: Diabetologia | Issue 10/2015

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Abstract

Aims/hypothesis

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/interpretation

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.
Appendix
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Metadata
Title
FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice
Authors
Kerstin Stemmer
Fabio Zani
Kirk M. Habegger
Christina Neff
Petra Kotzbeck
Michaela Bauer
Suma Yalamanchilli
Ali Azad
Maarit Lehti
Paulo J. F. Martins
Timo D. Müller
Paul T. Pfluger
Randy J. Seeley
Publication date
01-10-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 10/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-015-3668-7

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