Academic Journal
GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice.
| العنوان: | GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice. |
|---|---|
| المؤلفون: | Kim, Min Hee, Kim, Su-Jeong, Park, Woo-Jae, Lee, Dae Ho, Kim, Kyoung-Kon |
| المصدر: | BMC Pharmacology & Toxicology; 10/11/2024, Vol. 25 Issue 1, p1-14, 14p |
| مصطلحات موضوعية: | NON-alcoholic fatty liver disease, HEPATITIS, INSULIN resistance, FATTY liver, PEROXISOME proliferator-activated receptors, SEROTONIN receptors |
| مستخلص: | Background: The burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist. Methods: Male C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells. Results: After feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation. Conclusions: In summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases. [ABSTRACT FROM AUTHOR] |
| Copyright of BMC Pharmacology & Toxicology is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| قاعدة البيانات: | Complementary Index |
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Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Kim%2C+Min+Hee%22">Kim, Min Hee</searchLink><br /><searchLink fieldCode="AR" term="%22Kim%2C+Su-Jeong%22">Kim, Su-Jeong</searchLink><br /><searchLink fieldCode="AR" term="%22Park%2C+Woo-Jae%22">Park, Woo-Jae</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Dae+Ho%22">Lee, Dae Ho</searchLink><br /><searchLink fieldCode="AR" term="%22Kim%2C+Kyoung-Kon%22">Kim, Kyoung-Kon</searchLink> ) Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => BMC Pharmacology & Toxicology; 10/11/2024, Vol. 25 Issue 1, p1-14, 14p ) Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22NON-alcoholic+fatty+liver+disease%22">NON-alcoholic fatty liver disease</searchLink><br /><searchLink fieldCode="DE" term="%22HEPATITIS%22">HEPATITIS</searchLink><br /><searchLink fieldCode="DE" term="%22INSULIN+resistance%22">INSULIN resistance</searchLink><br /><searchLink fieldCode="DE" term="%22FATTY+liver%22">FATTY liver</searchLink><br /><searchLink fieldCode="DE" term="%22PEROXISOME+proliferator-activated+receptors%22">PEROXISOME proliferator-activated receptors</searchLink><br /><searchLink fieldCode="DE" term="%22SEROTONIN+receptors%22">SEROTONIN receptors</searchLink> ) Array ( [Name] => Abstract [Label] => Abstract [Group] => Ab [Data] => Background: The burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist. Methods: Male C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells. Results: After feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation. Conclusions: In summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases. [ABSTRACT FROM AUTHOR] ) Array ( [Name] => Abstract [Label] => [Group] => Ab [Data] => <i>Copyright of BMC Pharmacology & Toxicology is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) ) |
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