SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice

Kisoo Pahk, Sang Gil Lee, Chanmin Joung, Eun Ok Kim, Hyun Woo Kwon, Dong Hwi Kim, Jong Ik Hwang, Sungeun Kim, Won Ki Kim

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number112441
JournalBiomedicine and Pharmacotherapy
Volume145
DOIs
Publication statusPublished - 2022 Jan

Keywords

  • Inflammation
  • NAFLD
  • Obesity
  • Smad3
  • TGF-β
  • Visceral fat

ASJC Scopus subject areas

  • Pharmacology

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