Parthenolide, a feverfew-derived phytochemical, ameliorates obesity and obesity-induced inflammatory responses via the Nrf2/Keap1 pathway

Chae Young Kim; Bobin Kang; Hyung Joo Suh; Hyeon-Son Choi

doi:10.1016/j.phrs.2019.104259

Parthenolide, a feverfew-derived phytochemical, ameliorates obesity and obesity-induced inflammatory responses via the Nrf2/Keap1 pathway

Pharmacol Res. 2019 Jul:145:104259. doi: 10.1016/j.phrs.2019.104259. Epub 2019 May 9.

Authors

Chae Young Kim¹, Bobin Kang¹, Hyung Joo Suh², Hyeon-Son Choi³

Affiliations

¹ Department of Public Health Sciences, Korea University, Seoul, 07249, South Korea.
² Department of Public Health Sciences, Korea University, Seoul, 07249, South Korea. Electronic address: [email protected].
³ Department of Food Science and Technology, College of Natural Science, Seoul Women's University, Seoul, 139-774, South Korea. Electronic address: [email protected].

PMID: 31078744
DOI: 10.1016/j.phrs.2019.104259

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.

Keywords: Co-culture; Nrf2/Keap1 signaling; Obesity; Obesity-induced inflammatory response; Parthenolide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Animals
Anti-Inflammatory Agents* / pharmacology
Anti-Inflammatory Agents* / therapeutic use
Anti-Obesity Agents* / pharmacology
Anti-Obesity Agents* / therapeutic use
Diet, High-Fat
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism
Kelch-Like ECH-Associated Protein 1 / metabolism*
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Obesity / drug therapy*
Obesity / metabolism*
Phytochemicals / pharmacology
Phytochemicals / therapeutic use
RAW 264.7 Cells
Reactive Oxygen Species / metabolism
Sesquiterpenes* / pharmacology
Sesquiterpenes* / therapeutic use
Signal Transduction / drug effects
Tanacetum parthenium

Substances

Anti-Inflammatory Agents
Anti-Obesity Agents
Keap1 protein, mouse
Kelch-Like ECH-Associated Protein 1
Membrane Proteins
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Phytochemicals
Reactive Oxygen Species
Sesquiterpenes
parthenolide
Heme Oxygenase-1
Hmox1 protein, mouse