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FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice.
- Source :
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Diabetologia [Diabetologia] 2015 Oct; Vol. 58 (10), pp. 2414-23. Date of Electronic Publication: 2015 Jun 23. - Publication Year :
- 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.<br />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.<br />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.<br />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.<br />Competing Interests: Duality of interest R.J.S has received research support from Novo Nordisk, Ethicon Surgical Care, Eisai and Boehringer Ingelheim. R.J.S has served as a paid consultant for Novo Nordisk, Ethicon Surgical Care, Boehringer Ingelheim, Sanofi, Novartis, Takeda and has equity in Zafgen and Endobetix. All other authors declare no conflicts of interest.
- Subjects :
- Adipose Tissue metabolism
Animals
Fibroblast Growth Factors metabolism
Ketosis metabolism
Liver metabolism
Mice
Mice, Knockout
Neoplasms diet therapy
Neoplasms metabolism
Protein Deficiency metabolism
Diet, Ketogenic
Fibroblast Growth Factors genetics
Glucose metabolism
Homeostasis genetics
Ketosis genetics
Neoplasms genetics
Protein Deficiency genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0428
- Volume :
- 58
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 26099854
- Full Text :
- https://doi.org/10.1007/s00125-015-3668-7