دورية أكاديمية
أعرض في EDS

The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis.

التفاصيل البيبلوغرافية
العنوان: The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis.
المؤلفون: Antonellis PJ; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Droz BA; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Cosgrove R; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., O'Farrell LS; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Coskun T; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Perfield JW 2nd; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Bauer S; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Wade M; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Chouinard TE; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Brozinick JT; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Adams AC; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA., Samms RJ; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USA. Electronic address: samms_ricardo_j@lilly.com.
المصدر: Molecular metabolism [Mol Metab] 2019 Dec; Vol. 30, pp. 131-139. Date of Electronic Publication: 2019 Sep 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Fibroblast Growth Factors/*metabolism , Uncoupling Protein 1/*metabolism, 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
مستخلص: Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
(Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)
References: JAMA. 1999 Oct 27;282(16):1530-8. (PMID: 10546692)
Mol Endocrinol. 2010 Oct;24(10):2050-64. (PMID: 20667984)
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14379-84. (PMID: 19706524)
News Physiol Sci. 1999 Feb;14:24-29. (PMID: 11390813)
J Hepatol. 2019 Apr;70(4):735-744. (PMID: 30529590)
Cell Metab. 2017 Nov 7;26(5):709-718.e3. (PMID: 28988823)
Mol Metab. 2013 Oct 23;3(1):19-28. (PMID: 24567901)
N Engl J Med. 2007 Jan 18;356(3):213-5. (PMID: 17229948)
Peptides. 2007 Dec;28(12):2382-6. (PMID: 17996984)
Cell Metab. 2005 Oct;2(4):217-25. (PMID: 16213224)
J Hepatol. 2019 Mar;70(3):483-493. (PMID: 30414864)
J Clin Invest. 2013 Nov;123(11):4799-808. (PMID: 24084738)
Cell Rep. 2015 May 19;11(7):991-9. (PMID: 25956583)
Genes Dev. 2003 Jul 1;17(13):1581-91. (PMID: 12815072)
N Engl J Med. 2005 Mar 17;352(11):1138-45. (PMID: 15784668)
Endocrinology. 2004 Jun;145(6):2594-603. (PMID: 14976145)
Obes Surg. 2018 Mar;28(3):725-734. (PMID: 28861731)
Endocrinology. 2008 Dec;149(12):6018-27. (PMID: 18687777)
PLoS One. 2011 Mar 18;6(3):e17868. (PMID: 21437243)
Cell Metab. 2014 Oct 7;20(4):670-7. (PMID: 25130400)
JAMA. 2012 Feb 1;307(5):491-7. (PMID: 22253363)
Gastroenterology. 2001 Jul;121(1):91-100. (PMID: 11438497)
Mol Metab. 2012 Aug 28;2(1):31-7. (PMID: 24024127)
Lancet. 2018 Mar 24;391(10126):1174-1185. (PMID: 29519502)
Endocrinology. 2013 Jan;154(1):9-15. (PMID: 23183168)
Fluids Barriers CNS. 2013 Nov 01;10(1):32. (PMID: 24176017)
Cell Metab. 2012 Jan 4;15(1):19-24. (PMID: 22225873)
PLoS One. 2012;7(5):e38438. (PMID: 22675463)
Hepatology. 2019 Feb 25;:null. (PMID: 30805949)
Nature. 1997 May 1;387(6628):90-4. (PMID: 9139827)
J Clin Invest. 2005 Jun;115(6):1627-35. (PMID: 15902306)
Diabetes. 2010 Jul;59(7):1817-24. (PMID: 20357365)
J Lipid Res. 2007 Dec;48(12):2693-700. (PMID: 17823457)
Endocrinology. 2002 May;143(5):1741-7. (PMID: 11956156)
Nat Med. 2013 Sep;19(9):1147-52. (PMID: 23933984)
فهرسة مساهمة: Keywords: BAT; CYP7A1; FGF19; Metabolic; Thermogenesis; UCP1
المشرفين على المادة: 0 (Mitochondrial Proteins)
0 (Ucp1 protein, mouse)
0 (Uncoupling Protein 1)
0 (fibroblast growth factor 15, mouse)
62031-54-3 (Fibroblast Growth Factors)
تواريخ الأحداث: Date Created: 20191127 Date Completed: 20200623 Latest Revision: 20200623
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6807368
DOI: 10.1016/j.molmet.2019.09.006
PMID: 31767164
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2019.09.006