The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis.
Adipose Tissue, Brown
/ metabolism
Adipose Tissue, White
/ metabolism
Animals
Body Weight
Diabetes Mellitus, Experimental
/ metabolism
Diet, High-Fat
Energy Metabolism
Fibroblast Growth Factors
/ genetics
Insulin Resistance
Lipid Metabolism
Lipogenesis
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Obese
Mitochondria
/ metabolism
Mitochondrial Proteins
/ metabolism
Obesity
/ metabolism
Thermogenesis
Uncoupling Protein 1
/ genetics
BAT
CYP7A1
FGF19
Metabolic
Thermogenesis
UCP1
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
01
08
2019
revised:
29
08
2019
accepted:
13
09
2019
entrez:
27
11
2019
pubmed:
27
11
2019
medline:
24
6
2020
Statut:
ppublish
Résumé
Fibroblast growth factor 19 (FGF19) is a postprandial hormone which plays diverse roles in the regulation of bile acid, glucose, and lipid metabolism. Administration of FGF19 to obese/diabetic mice lowers body weight, improves insulin sensitivity, and enhances glycemic control. The primary target organ of FGF19 is the liver, where it regulates bile acid homeostasis in response to nutrient absorption. In contrast, the broader pharmacologic actions of FGF19 are proposed to be driven, in part, by the recruitment of the thermogenic protein uncoupling protein 1 (UCP1) in white and brown adipose tissue. However, the precise contribution of UCP1-dependent thermogenesis to the therapeutic actions of FGF19 has not been critically evaluated. Using WT and germline UCP1 knockout mice, the primary objective of the current investigation was to determine the in vivo pharmacology of FGF19, focusing on its thermogenic and anti-obesity activity. We report that FGF19 induced mRNA expression of UCP1 in adipose tissue and show that this effect is required for FGF19 to increase caloric expenditure. However, we demonstrate that neither UCP1 induction nor an elevation in caloric expenditure are necessary for FGF19 to induce weight loss in obese mice. In contrast, the anti-obesity action of FGF19 appeared to be associated with its known physiological role. In mice treated with FGF19, there was a significant reduction in the mRNA expression of genes associated with hepatic bile acid synthesis enzymes, lowered levels of hepatic bile acid species, and a significant increase in fecal energy content, all indicative of reduced lipid absorption in animals treated with FGF19. Taken together, we report that the anti-obesity effect of FGF19 occurs in the absence of UCP1. Our data suggest that the primary way in which exogenous FGF19 lowers body weight in mice may be through the inhibition of bile acid synthesis and subsequently a reduction of dietary lipid absorption.
Identifiants
pubmed: 31767164
pii: S2212-8778(19)30909-3
doi: 10.1016/j.molmet.2019.09.006
pmc: PMC6807368
pii:
doi:
Substances chimiques
Mitochondrial Proteins
0
Ucp1 protein, mouse
0
Uncoupling Protein 1
0
fibroblast growth factor 15, mouse
0
Fibroblast Growth Factors
62031-54-3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
131-139Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.
Références
JAMA. 1999 Oct 27;282(16):1530-8
pubmed: 10546692
Mol Endocrinol. 2010 Oct;24(10):2050-64
pubmed: 20667984
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14379-84
pubmed: 19706524
News Physiol Sci. 1999 Feb;14:24-29
pubmed: 11390813
J Hepatol. 2019 Apr;70(4):735-744
pubmed: 30529590
Cell Metab. 2017 Nov 7;26(5):709-718.e3
pubmed: 28988823
Mol Metab. 2013 Oct 23;3(1):19-28
pubmed: 24567901
N Engl J Med. 2007 Jan 18;356(3):213-5
pubmed: 17229948
Peptides. 2007 Dec;28(12):2382-6
pubmed: 17996984
Cell Metab. 2005 Oct;2(4):217-25
pubmed: 16213224
J Hepatol. 2019 Mar;70(3):483-493
pubmed: 30414864
J Clin Invest. 2013 Nov;123(11):4799-808
pubmed: 24084738
Cell Rep. 2015 May 19;11(7):991-9
pubmed: 25956583
Genes Dev. 2003 Jul 1;17(13):1581-91
pubmed: 12815072
N Engl J Med. 2005 Mar 17;352(11):1138-45
pubmed: 15784668
Endocrinology. 2004 Jun;145(6):2594-603
pubmed: 14976145
Obes Surg. 2018 Mar;28(3):725-734
pubmed: 28861731
Endocrinology. 2008 Dec;149(12):6018-27
pubmed: 18687777
PLoS One. 2011 Mar 18;6(3):e17868
pubmed: 21437243
Cell Metab. 2014 Oct 7;20(4):670-7
pubmed: 25130400
JAMA. 2012 Feb 1;307(5):491-7
pubmed: 22253363
Gastroenterology. 2001 Jul;121(1):91-100
pubmed: 11438497
Mol Metab. 2012 Aug 28;2(1):31-7
pubmed: 24024127
Lancet. 2018 Mar 24;391(10126):1174-1185
pubmed: 29519502
Endocrinology. 2013 Jan;154(1):9-15
pubmed: 23183168
Fluids Barriers CNS. 2013 Nov 01;10(1):32
pubmed: 24176017
Cell Metab. 2012 Jan 4;15(1):19-24
pubmed: 22225873
PLoS One. 2012;7(5):e38438
pubmed: 22675463
Hepatology. 2019 Feb 25;:null
pubmed: 30805949
Nature. 1997 May 1;387(6628):90-4
pubmed: 9139827
J Clin Invest. 2005 Jun;115(6):1627-35
pubmed: 15902306
Diabetes. 2010 Jul;59(7):1817-24
pubmed: 20357365
J Lipid Res. 2007 Dec;48(12):2693-700
pubmed: 17823457
Endocrinology. 2002 May;143(5):1741-7
pubmed: 11956156
Nat Med. 2013 Sep;19(9):1147-52
pubmed: 23933984