title: Butein induction of HO-1 by p38 MAPK/Nrf2 pathway in adipocytes attenuates high-fat diet induced adipose hypertrophy in mice.
abstract: Adipose tissue inflammation and oxidative stress are key components in the development of obesity and insulin resistance. Heme oxygenase (HO)-1 in adipocytes protects against obesity and adipose dysfunction. In this study, we report the identification of butein, a flavonoid chalcone, as a novel inducer of HO-1 expression in adipocytes in vitro and in vivo. Butein upregulated HO-1 mRNA and protein expression in 3T3-L1 adipocytes, accompanied by Kelch-Like ECH-Associated Protein (Keap) 1 degradation and increase in the nuclear level of nuclear factor erythroid 2-related factor 2 (Nrf2). Butein modulation of Keap1 and Nrf2 as well as HO-1 upregulation was reversed by pretreatment with p38 MAPK inhibitor SB203580, indicating the involvement of p38 MAPK in butein activation of Nrf2 in adipocytes. In addition, HO-1 activation by butein led to the inhibitions of reactive oxygen species and adipocyte differentiation, as evidenced by the fact that butein repression of reactive oxygen species and adipogenesis was reversed by pretreatment with HO-1 inhibitor SnPP. Induction of HO-1 expression by butein was also demonstrated in the adipose tissue of C57BL/6 mice fed a high-fat diet administered along with butein for three weeks, and correlated with the inhibitions of adiposity and adipose tissue inflammation, which were reversed by co-administration of SnPP. Altogether, our results demonstrate that butein activates the p38 MAPK/Nrf2/HO-1 pathway to act as a potent inhibitor of adipose hypertrophy and inflammation in a diet-induced obesity model and thus has potential for suppressing obesity-linked metabolic syndrome.
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Chonbuk National University Medical School, Jeonju-si, Jeollabuk-do, Republic of Korea.
authors.forename: Sun-O
authors.initials: SO
authors.lastname: Ka
authors.affiliation: Chonbuk National University Medical School, Jeonju-si, Jeollabuk-do, Republic of Korea.
authors.forename: Youngyi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Chonbuk National University Medical School, Jeonju-si, Jeollabuk-do, Republic of Korea.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Woosuk University, Wanju-gun, Jeollabuk-do, Republic of Korea. Electronic address: ejbae@woosuk.ac.kr.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Bae
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005951:Glucose Tolerance Test; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C040918:butein; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Adipose hypertrophy; Butein; Glucose intolerance; HO-1; Nrf2; P38 MAPK