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Endocrine

pp 1–14 | Cite as

Liver-derived FGF21 is essential for full adaptation to ketogenic diet but does not regulate glucose homeostasis

  • Mikiko Watanabe
  • Garima Singhal
  • Ffolliott M. Fisher
  • Thomas C. Beck
  • Donald A. Morgan
  • Fabio Socciarelli
  • Marie L. Mather
  • Renata Risi
  • Jared Bourke
  • Kamal Rahmouni
  • Owen P. McGuinness
  • Jeffrey S. Flier
  • Eleftheria Maratos-FlierEmail author
Original Article

Abstract

Background

Fibroblast growth factor 21 (FGF21) is expressed in several metabolically active tissues, including liver, fat, and acinar pancreas, and has pleiotropic effects on metabolic homeostasis. The dominant source of FGF21 in the circulation is the liver.

Objective and methods

To analyze the physiological functions of hepatic FGF21, we generated a hepatocyte-specific knockout model (LKO) by mating albumin-Cre mice with FGF21 flox/flox (fl/fl) mice and challenged it with different nutritional models.

Results

Mice fed a ketogenic diet typically show increased energy expenditure; this effect was attenuated in LKO mice. LKO on KD also developed hepatic pathology and altered hepatic lipid homeostasis. When evaluated using hyperinsulinemic-euglycemic clamps, glucose infusion rates, hepatic glucose production, and glucose uptake were similar between fl/fl and LKO DIO mice.

Conclusions

We conclude that liver-derived FGF21 is important for complete adaptation to ketosis but has a more limited role in the regulation of glycemic homeostasis.

Keywords

Fibroblast Growth Factor 21 Ketogenic diet Nonalcoholic fatty liver disease Cholesterol Energy metabolism Adipose tissue 

Abbreviations

FGF21

Fibroblast growth factor 21

fl/fl

Flox/flox

LKO

FGF21 liver-specific knockout

KD

Ketogenic diet

HFD

High fat diet

PPAR α

Peroxisome proliferator-activated receptor α

FGF21KO

Fibroblast growth factor 21 knockout

WT

Wild type

IP

Intraperitoneal

[2-14C]D-G

[2-14C]D-glucose

RG

Glucose metabolic Index

SEM

Standard error of the mean

CLAMS

Comprehensive lab animal monitoring system oxymax

qNMR

Quantitative nuclear magnetic resonance

ALT

Alanine aminotransferase

PGK

PhosphoGlycerate Kinase

NAFLD

Nonalcoholic fatty liver disease

BAT

Brown adipose tissue

UCP1

Uncoupling protein 1

SNA

Sympathetic nerve activity

ANOVA

Analysis of variance

KLB

β-Klotho

EWAT

Epididymal white adipose tissue

IWAT

Inguinal white adipose tissue

ipGTT

Intraperitoneal glucose tolerance test

ITT

Insulin tolerance test

RER

Respiratory exchange ratio

MCD

Methionine choline deficient

SNS

Sympathetic nervous system

DIO

Diet induced obesity

FAS

Fatty acids synthase

SCD-1

Stearoyl-CoA desaturase

CD36

Cluster of differentiation 36

LCAD

Long chain acyl-CoA dehydrogenase

VLCAD

Very long chain acyl-CoA dehydrogenase

ACOX1

Peroxisomal acyl-coenzyme A oxidase 1

CPT1α

Carnitine palmitoyltransferase I α

PPAR

Peroxisome proliferator-activated receptor

PGC1 α

Peroxisome proliferator-activated receptor (PPAR) γ Coactivator 1α

PGC1 β

Peroxisome proliferator-activated receptor (PPAR) γ Coactivator 1β

ABCG5

ATP-binding cassette sub-family G member 5

ABCG8

ATP-binding cassette sub-family G member 8

LXR

Liver X receptor

Cyp7A1

Cytochrome P450 7A1,

SHP

Small heterodimer partner

HMGCS1

3-hydroxy-3-methylglutaryl-CoA synthase

HMGCR

3-hydroxy-3-methylglutaryl-CoA reductase

SREBP2

Sterol regulatory element-binding protein 2

PCSK9

Proprotein convertase subtilisin/kexin type 9

LDLR

LDL receptor

TGF1 β

Transforming growth factor 1 β

MCP1

Monocyte chemoattractant protein-1

MMP2

Matrix metalloproteinase-2

SMA

Smooth muscle actin

IL1 β

Interleukin 1 β

TIMP

Metallopeptidase inhibitor 1

Notes

Acknowledgements

We thank Dr Pavlos Pissios for scientific discussions and Dr Thomas Webb for technical assistance.

Author contributions

G.S., F.M.F., T.C.B., O.P.M., J.S.F. and E.M.F. conceived and designed the experiments. M.W., G.S., J.B., M.M., T.C.B., D.A.M. and R.R. and Vanderbilt MMPC performed the experiments. M.W., G.S., F.M.F., T.C.B., F.S., O.P.M. analyzed the data. E.M.F., J.S.F., F.M.F., K.R. and O.P.M. contributed with reagents/materials/analysis tools/critical revisions. M.W., G.S. and E.M.F. drafted the manuscript.

Funding

This work was supported by NIH Grant DK028082 (to E.M.F. and J.S.F.). M.W. was supported by funds from The Rotary Club of Rome. We are grateful for the help from the HDDC Core supported by NIH Grant NIDDK P30 DK034854. Generation of genetically altered floxed mice was made under the auspices of BADERC 5P30DK057521 and the BNORC 5P30DK046200. K.R was supported by funds from the NIH (HL084207), the American Heart Association (14EIA18860041) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center. O.P.M. was supported by funds from the NIH (DK059637). The Vanderbilt Mouse Metabolic Phenotyping Center (DK059637) and the Hormone Assay and Analytical Services Core (DK059637 and DK020593) provided surgical and analytical support for clamp studies.

Supplementary material

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Supplementary Information
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Supplementary Information
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Supplementary Information
12020_2019_2124_MOESM4_ESM.docx (14 kb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mikiko Watanabe
    • 1
    • 2
  • Garima Singhal
    • 1
  • Ffolliott M. Fisher
    • 1
  • Thomas C. Beck
    • 3
  • Donald A. Morgan
    • 4
  • Fabio Socciarelli
    • 5
  • Marie L. Mather
    • 1
  • Renata Risi
    • 2
  • Jared Bourke
    • 1
  • Kamal Rahmouni
    • 4
  • Owen P. McGuinness
    • 3
  • Jeffrey S. Flier
    • 1
    • 6
  • Eleftheria Maratos-Flier
    • 1
    Email author
  1. 1.Department of Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and EndocrinologySapienza University of RomeRomeItaly
  3. 3.Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA
  4. 4.Department of PharmacologyUniversity of Iowa Carver College of MedicineIowa CityUSA
  5. 5.Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  6. 6.Department of NeurobiologyHarvard Medical SchoolBostonUSA

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