Liver-derived FGF21 is essential for full adaptation to ketogenic diet but does not regulate glucose homeostasis.
Adipose tissue
Cholesterol
Energy metabolism
Fibroblast Growth Factor 21
Ketogenic diet
Nonalcoholic fatty liver disease
Journal
Endocrine
ISSN: 1559-0100
Titre abrégé: Endocrine
Pays: United States
ID NLM: 9434444
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
06
08
2019
accepted:
22
10
2019
pubmed:
16
11
2019
medline:
22
6
2021
entrez:
16
11
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31728756
doi: 10.1007/s12020-019-02124-3
pii: 10.1007/s12020-019-02124-3
pmc: PMC7948212
mid: NIHMS1543198
doi:
Substances chimiques
fibroblast growth factor 21
0
Fibroblast Growth Factors
62031-54-3
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
95-108Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK078188
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020593
Pays : United States
Organisme : American Heart Association
ID : 14EIA18860041
Pays : International
Organisme : NIDDK NIH HHS
ID : P30 DK058404
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK028082
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK046200
Pays : United States
Organisme : NIH HHS
ID : DK028082
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK057521
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK054759
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK043748
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK059637
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK028082
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020593
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL084207
Pays : United States
Références
Gastroenterology. 2014 Nov;147(5):1073-83.e6
pubmed: 25083607
Mol Metab. 2018 Jul;13:56-66
pubmed: 29753678
Trends Endocrinol Metab. 2015 Nov;26(11):608-617
pubmed: 26490383
Mol Metab. 2017 Nov;6(11):1395-1406
pubmed: 29107287
Diabetes. 2014 Dec;63(12):4057-63
pubmed: 25008183
Am J Physiol Renal Physiol. 2005 Nov;289(5):F1088-95
pubmed: 15998839
Mol Metab. 2016 May 18;5(8):690-698
pubmed: 27656406
Cell Metab. 2007 Jun;5(6):426-37
pubmed: 17550778
Diabetes. 2010 Nov;59(11):2781-9
pubmed: 20682689
Diabetes. 2006 Feb;55(2):390-7
pubmed: 16443772
Cell Metab. 2016 Sep 13;24(3):348-360
pubmed: 27626191
Nat Commun. 2018 Jan 18;9(1):272
pubmed: 29348470
Mol Metab. 2016 Nov 21;6(1):2-9
pubmed: 28123930
Mol Metab. 2018 Oct;16:116-125
pubmed: 30005879
Cell Metab. 2016 Mar 8;23(3):427-40
pubmed: 26959184
Hypertension. 2017 Nov;70(5):990-997
pubmed: 28874461
Endocrinology. 2009 Sep;150(9):4084-93
pubmed: 19470704
Obes Surg. 2018 Apr;28(4):1109-1116
pubmed: 29098545
Cell Metab. 2007 Jun;5(6):415-25
pubmed: 17550777
J Clin Invest. 2002 Oct;110(7):905-11
pubmed: 12370266
Cold Spring Harb Perspect Biol. 2011 Jul 01;3(7):
pubmed: 21504873
Hepatology. 2011 Mar;53(3):810-20
pubmed: 21319198
J Vis Exp. 2011 Nov 16;(57):
pubmed: 22126863
J Endocrinol. 2018 May;237(2):139-152
pubmed: 29615519
Endocrinology. 2013 Sep;154(9):3099-109
pubmed: 23766126
Cell Metab. 2018 Oct 2;28(4):656-666.e1
pubmed: 30017358
J Biol Chem. 1957 May;226(1):497-509
pubmed: 13428781
Cell Metab. 2005 Oct;2(4):217-25
pubmed: 16213224
Mol Metab. 2014 Oct 08;4(1):51-7
pubmed: 25685689
Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2056-65
pubmed: 26170063
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1105-14
pubmed: 19706786
Annu Rev Physiol. 2006;68:159-91
pubmed: 16460270
Cell Metab. 2013 Sep 3;18(3):333-40
pubmed: 24011069
Diabetes. 2018 Nov;67(11):2213-2226
pubmed: 30104247
Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1724-39
pubmed: 17299079
Mol Metab. 2016 Nov 23;6(1):14-21
pubmed: 28123933
Endocrinology. 2008 Dec;149(12):6018-27
pubmed: 18687777
Hepatology. 2014 Sep;60(3):977-89
pubmed: 24590984
IUBMB Life. 2013 Aug;65(8):675-84
pubmed: 23847008
Carcinogenesis. 2006 Jul;27(7):1334-40
pubmed: 16501253
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6500-5
pubmed: 11344269
Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10853-8
pubmed: 19541642
Annu Rev Physiol. 2016;78:223-41
pubmed: 26654352
PLoS One. 2012;7(1):e30160
pubmed: 22276152
Cell Rep. 2016 Mar 15;14(10):2273-80
pubmed: 26947074
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1197-204
pubmed: 19738035
Hepatology. 2011 Jan;53(1):325-35
pubmed: 21254180
PLoS One. 2016 Feb 12;11(2):e0148252
pubmed: 26872145
J Clin Invest. 2005 Jun;115(6):1627-35
pubmed: 15902306
Endocrinology. 2009 Nov;150(11):4931-40
pubmed: 19819944
EBioMedicine. 2017 Feb;15:173-183
pubmed: 28041926
Endocrinology. 2015 Jul;156(7):2470-81
pubmed: 25924103
Am J Physiol. 1985 Mar;248(3 Pt 1):E353-62
pubmed: 3883806
Genes Dev. 2012 Feb 1;26(3):271-81
pubmed: 22302939