The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis
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 primar...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-12-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819309093 |
| _version_ | 1818505098706288640 |
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| author | Patrick J. Antonellis Brian A. Droz Richard Cosgrove Libbey S. O'Farrell Tamer Coskun James W. Perfield, II Steven Bauer Mark Wade Tara E. Chouinard Joseph T. Brozinick Andrew C. Adams Ricardo J. Samms |
| author_facet | Patrick J. Antonellis Brian A. Droz Richard Cosgrove Libbey S. O'Farrell Tamer Coskun James W. Perfield, II Steven Bauer Mark Wade Tara E. Chouinard Joseph T. Brozinick Andrew C. Adams Ricardo J. Samms |
| author_sort | Patrick J. Antonellis |
| collection | DOAJ |
| description | 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. Keywords: FGF19, Thermogenesis, UCP1, Metabolic, BAT, CYP7A1 |
| first_indexed | 2024-12-10T21:46:07Z |
| format | Article |
| id | doaj.art-f1ef67a9a6a44312b87faed6aa256893 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-10T21:46:07Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-f1ef67a9a6a44312b87faed6aa2568932022-12-22T01:32:22ZengElsevierMolecular Metabolism2212-87782019-12-0130131139The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesisPatrick J. Antonellis0Brian A. Droz1Richard Cosgrove2Libbey S. O'Farrell3Tamer Coskun4James W. Perfield, II5Steven Bauer6Mark Wade7Tara E. Chouinard8Joseph T. Brozinick9Andrew C. Adams10Ricardo J. Samms11Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USALilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USACorresponding author. Diabetes Research, Eli Lilly and Company, Lilly Research Laboratories, USA.; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, 46285, USAObjective: 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. Keywords: FGF19, Thermogenesis, UCP1, Metabolic, BAT, CYP7A1http://www.sciencedirect.com/science/article/pii/S2212877819309093 |
| spellingShingle | Patrick J. Antonellis Brian A. Droz Richard Cosgrove Libbey S. O'Farrell Tamer Coskun James W. Perfield, II Steven Bauer Mark Wade Tara E. Chouinard Joseph T. Brozinick Andrew C. Adams Ricardo J. Samms The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis Molecular Metabolism |
| title | The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis |
| title_full | The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis |
| title_fullStr | The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis |
| title_full_unstemmed | The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis |
| title_short | The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis |
| title_sort | anti obesity effect of fgf19 does not require ucp1 dependent thermogenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2212877819309093 |
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