title: Magnolia bioactive constituent 4-O-methylhonokiol prevents the impairment of cardiac insulin signaling and the cardiac pathogenesis in high-fat diet-induced obese mice.
abstract: In obesity, cardiac insulin resistance is a putative cause of cardiac hypertrophy and dysfunction. In our previous study, we observed that Magnolia extract BL153 attenuated high-fat-diet (HFD)-induced cardiac pathogenic changes. In this study, we further investigated the protective effects of the BL153 bioactive constituent, 4-O-methylhonokiol (MH), against HFD-induced cardiac pathogenesis and its possible mechanisms. C57BL/6J mice were fed a normal diet or a HFD with gavage administration of vehicle, BL153, or MH (low or high dose) daily for 24 weeks. Treatment with MH attenuated HFD-induced obesity, as evidenced by body weight gain, and cardiac pathogenesis, as assessed by the heart weight and echocardiography. Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling. MH also inhibited cardiac expression of the inflammatory factors tumor necrosis factor-α and plasminogen activator inhibitor-1 and increased the phosphorylation of nuclear factor erythroid-derived 2-like 2 (Nrf2) as well as the expression of a Nrf2 downstream target gene heme oxygenase-1. The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels. Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein. These results suggest that MH, a bioactive constituent of Magnolia, prevents HFD-induced cardiac pathogenesis by attenuating the impairment of cardiac insulin signaling, perhaps via activation of Nrf2 and Akt2 signaling to attenuate CD36-mediated lipid accumulation and lipotoxicity.
authors.affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China ; 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China ; 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China ; 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cai
authors.affiliation: 4. Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Conklin
authors.affiliation: 5. Bioland Biotec HaiMen Co., Ltd, Linjiang New District, Haomen, 226100, China.
authors.forename: Ki-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: 6. KHBios, 505 Venture Center, 194-41, Osongsaengmyeong 1, Osong, Cheongju, Chungbuk 363-951, Republic of Korea.
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 1. Department of Cardiology at the First Hospital of Jilin University, Changchun, 130021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 7. Bioland R&D Center, 59 Songjeongni 2-gil, Byeongcheon, Dongnam, Cheonan, Chungnam 330-863, Republic of Korea.
authors.forename: Young Heui
authors.initials: YH
authors.lastname: Kim
authors.affiliation: 2. The Chinese-American Research Institute for Diabetic Complications and the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China ; 3. Kosair Children's Hospital Research Institute, Department of Pediatrics of University of Louisville, Louisville, KY 40202.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D059305:Diet, High-Fat; D006334:Heart Function Tests / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D017705:Lignans / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C542058:4-O-methylhonokiol; D001713:Biphenyl Compounds; D007328:Insulin; D017705:Lignans
keywords: 4-O-methylhonokiol; Nrf2; cardiac insulin signaling; lipid accumulation; lipotoxicity; obesity