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

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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.

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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

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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.

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Author notes

  1. These authors contributed equally: Mikiko Watanabe, Garima Singhal

Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Mikiko Watanabe, Garima Singhal, Ffolliott M. Fisher, Marie L. Mather, Jared Bourke, Jeffrey S. Flier & Eleftheria Maratos-Flier

  2. Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy

    Mikiko Watanabe & Renata Risi

  3. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Thomas C. Beck & Owen P. McGuinness

  4. Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Donald A. Morgan & Kamal Rahmouni

  5. Department of Oncology-Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden

    Fabio Socciarelli

  6. Department of Neurobiology, Harvard Medical School, Boston, MA, 02215, USA

    Jeffrey S. Flier

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  1. Mikiko Watanabe
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Correspondence to Eleftheria Maratos-Flier.

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Watanabe, M., Singhal, G., Fisher, F.M. et al. Liver-derived FGF21 is essential for full adaptation to ketogenic diet but does not regulate glucose homeostasis. Endocrine 67, 95–108 (2020). https://doi.org/10.1007/s12020-019-02124-3

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