SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice
Objective: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signali...
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Elsevier
2022
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oai:doaj.org-article:a9ea870b08bb456f92e9402c01fb592c2021-11-22T04:17:45ZSP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice0753-332210.1016/j.biopha.2021.112441https://doaj.org/article/a9ea870b08bb456f92e9402c01fb592c2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012270https://doaj.org/toc/0753-3322Objective: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. Methods: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. Key findings: SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. Conclusion: Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.Kisoo PahkSang Gil LeeChanmin JoungEun-Ok KimHyun Woo KwonDong Hwi KimJong-Ik HwangSungeun KimWon-Ki KimElsevierarticleObesityNAFLDTGF-βSmad3InflammationVisceral fatTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112441- (2022) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Obesity NAFLD TGF-β Smad3 Inflammation Visceral fat Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
Obesity NAFLD TGF-β Smad3 Inflammation Visceral fat Therapeutics. Pharmacology RM1-950 Kisoo Pahk Sang Gil Lee Chanmin Joung Eun-Ok Kim Hyun Woo Kwon Dong Hwi Kim Jong-Ik Hwang Sungeun Kim Won-Ki Kim SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| description |
Objective: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. Methods: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. Key findings: SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. Conclusion: Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT. |
| format |
article |
| author |
Kisoo Pahk Sang Gil Lee Chanmin Joung Eun-Ok Kim Hyun Woo Kwon Dong Hwi Kim Jong-Ik Hwang Sungeun Kim Won-Ki Kim |
| author_facet |
Kisoo Pahk Sang Gil Lee Chanmin Joung Eun-Ok Kim Hyun Woo Kwon Dong Hwi Kim Jong-Ik Hwang Sungeun Kim Won-Ki Kim |
| author_sort |
Kisoo Pahk |
| title |
SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| title_short |
SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| title_full |
SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| title_fullStr |
SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| title_full_unstemmed |
SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| title_sort |
sp-1154, a novel synthetic tgf-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice |
| publisher |
Elsevier |
| publishDate |
2022 |
| url |
https://doaj.org/article/a9ea870b08bb456f92e9402c01fb592c |
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