Parthenolide, a feverfew-derived phytochemical, ameliorates obesity and obesity-induced inflammatory responses via the Nrf2/Keap1 pathway. (July 2019)

• Record Type: Journal Article
• Authors: Kim, Chae Young; Kang, Bobin; Suh, Hyung Joo; Choi, Hyeon-Son
• Is Part Of: Pharmacological research. Volume 145(2019)
• Publication Date: 2019-07
• Subjects: ATM adipose tissue macrophage -- CD11c complement component 3 receptor 4 subunit -- CD206 cluster of differentiation 206 -- Gpx glutathione peroxidase -- GR glutathione reductase -- GSH glutathione -- GST glutathione-s-transferase -- HFD high fat diet -- H&E Hematoxylin and eosin -- HO-1 hemoxygenase-1 -- IHC Immunohistochemistry -- IL-6 interleukin-6 -- MDA malondialdehyde -- MAPK mitogen-activated protein kinase -- MCP-1 monocyte Chemoattractant Protein-1 -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NLRP3 NLR Family Pyrin Domain Containing 3 -- Nrf2/Keap1 nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 -- PL Parthenolide -- RAW-CM macrophage-conditioned medium -- SOD1 superoxide dismutase 1 -- SVF stroma vascular fraction -- 3T3-CM adipocyte-conditioned medium -- TNF-α tumor necrosis factor-alpha -- siRNA small interfering RNA -- WAT white adipose tissues -- eWAT epididymal WAT -- iWAT inguinal WAT -- mWAT mesenteric WAT; Parthenolide -- Co-culture -- Obesity -- Obesity-induced inflammatory response -- Nrf2/Keap1 signaling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104259
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: PL inhibited obesity and the inflammatory/oxidative responses in vitro and in vivo . This PL-mediated inhibitory effect on obesity-induced inflammatory responses was shown to be exerted via the Nrf2/Keap1 signaling pathway. PL-mediated anti-inflammatory status was associated with the modulation of M1 and M2 phenotypes in obesity. Parthenolide inhibited adipocyte-mediated inflammatory responses in co-culture system, and suppressed HFD-induced obesity and obesity-induced inflammatory and oxidative stress responses with the increase of antioxidant responses in mice by activating Nrf2-Keap1 signaling pathway. Abstract: Parthenolide (PL) is one of the most abundant sesquiterpene lactones found in the plant feverfew ( Tanacetum parthenium (L.) Sch.Bip.). PL was investigated for its effect on obesity and obesity-induced inflammatory/oxidant responses in vitro and in vivo . An obesity-induced inflammatory response was induced in various co-culture systems using adipocytes (3T3-L1) and macrophages (RAW264.7) in vitro and the effect of PL and its mechanism of action were determined. PL effectively suppressed the adiposity-induced inflammatory responses by downregulating IL-6 (40–42%) and MCP-1 (26–37%) in 3T3-CM-cultured macrophages and contact co-culture system. PL also favorably regulated the dysregulations of adiponectin and resistin in macrophage-conditioned medium (RAW-CM)-cultured adipocytes. In transwell system of adipocyte and macrophage, PL was shown to upregulated Nrf2 and its target molecule, HO-1 by promoting nuclear translocation of Nrf2. In particular, in siRNA knockdown study, the PL-mediated anti-inflammatory response was exerted via the Nrf2/Keap1 pathway. In animal study using high-fat diet (HFD)-fed mice, PL-administered mice showed a significant reduction in body weight and white adipose tissues (WATs). This PL-mediated anti-obese effect was connected to anti-inflammatory responses with the regulation of inflammatory cytokines, and the downregulation of NF-κB and MAPKs. Furthermore, PL differentially modulated CD11c and CD206, which are pro-/anti-inflammatory phenotypes of ATMs, in stroma vascular fraction (SVF) and immunohistochemistry (IHC) staining analyses. PL also regulated the level of (anti)oxidant molecules with the activation of Nrf2/Keap1signaling. Taken together, PL inhibited obesity and obesity-induced inflammatory responses via the activation of Nrf2/Keap1 signaling, indicating a potential of PL as a functional agent to control obesity-related diseases.