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Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model

Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 we...

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Autores principales: Schwartzkopf, Chad D., Hadcock, John R., Liu, Guang, Germano, Peter, Roux, Julien, Shea, Courtney M., Buys, Emmanuel S., Jones, Juli E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931041/
https://www.ncbi.nlm.nih.gov/pubmed/35308230
http://dx.doi.org/10.3389/fphar.2022.852080
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author Schwartzkopf, Chad D.
Hadcock, John R.
Liu, Guang
Germano, Peter
Roux, Julien
Shea, Courtney M.
Buys, Emmanuel S.
Jones, Juli E.
author_facet Schwartzkopf, Chad D.
Hadcock, John R.
Liu, Guang
Germano, Peter
Roux, Julien
Shea, Courtney M.
Buys, Emmanuel S.
Jones, Juli E.
author_sort Schwartzkopf, Chad D.
collection PubMed
description Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed on 60% high-fat diet (HFD, DIO mice). At 14 weeks old, the DIO mice were either maintained on HFD or switched to HFD with praliciguat (6-mg/kg). Day 28 samples were collected for biomarker analysis. In a second study under the same paradigm, indirect calorimetry was performed on days 8, 9, 20, 21, 32, and 33 and an oral lipid tolerance test (LTT) on day 38. Mice treated 28 days with praliciguat had lower levels of fasting plasma insulin, C-peptide, triglycerides, and HOMA-IR (homeostatic model assessment for insulin resistance) than DIO controls. In addition, energy expenditure was higher in praliciguat-treated than in DIO control mice on days 9, 20, 32, and 33; and day-38 triglycerides were lower. HFD-induced increases in gene expression of liver TNF-ɑ, lipoprotein lipase (Lpl), and patatin-like phospholipase domain-containing protein 3 (Pnpla3) in control DIO mice were attenuated in praliciguat-treated DIO mice. The positive metabolic effects observed in praliciguat-treated mice were associated with the restoration of liver PI3K (pAKT-Thr308) signaling, but not MAPK (pERK). In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with praliciguat treatment in DIO mice.
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spelling pubmed-89310412022-03-19 Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model Schwartzkopf, Chad D. Hadcock, John R. Liu, Guang Germano, Peter Roux, Julien Shea, Courtney M. Buys, Emmanuel S. Jones, Juli E. Front Pharmacol Pharmacology Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed on 60% high-fat diet (HFD, DIO mice). At 14 weeks old, the DIO mice were either maintained on HFD or switched to HFD with praliciguat (6-mg/kg). Day 28 samples were collected for biomarker analysis. In a second study under the same paradigm, indirect calorimetry was performed on days 8, 9, 20, 21, 32, and 33 and an oral lipid tolerance test (LTT) on day 38. Mice treated 28 days with praliciguat had lower levels of fasting plasma insulin, C-peptide, triglycerides, and HOMA-IR (homeostatic model assessment for insulin resistance) than DIO controls. In addition, energy expenditure was higher in praliciguat-treated than in DIO control mice on days 9, 20, 32, and 33; and day-38 triglycerides were lower. HFD-induced increases in gene expression of liver TNF-ɑ, lipoprotein lipase (Lpl), and patatin-like phospholipase domain-containing protein 3 (Pnpla3) in control DIO mice were attenuated in praliciguat-treated DIO mice. The positive metabolic effects observed in praliciguat-treated mice were associated with the restoration of liver PI3K (pAKT-Thr308) signaling, but not MAPK (pERK). In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with praliciguat treatment in DIO mice. Frontiers Media S.A. 2022-03-04 /pmc/articles/PMC8931041/ /pubmed/35308230 http://dx.doi.org/10.3389/fphar.2022.852080 Text en Copyright © 2022 Schwartzkopf, Hadcock, Liu, Germano, Roux, Shea, Buys and Jones. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Schwartzkopf, Chad D.
Hadcock, John R.
Liu, Guang
Germano, Peter
Roux, Julien
Shea, Courtney M.
Buys, Emmanuel S.
Jones, Juli E.
Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title_full Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title_fullStr Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title_full_unstemmed Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title_short Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model
title_sort beneficial metabolic effects of praliciguat, a soluble guanylate cyclase stimulator, in a mouse diet-induced obesity model
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931041/
https://www.ncbi.nlm.nih.gov/pubmed/35308230
http://dx.doi.org/10.3389/fphar.2022.852080
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