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Int J Biol Sci 2015; 11(8):879-891. doi:10.7150/ijbs.12101

Research Paper

Magnolia Bioactive Constituent 4-O-Methylhonokiol Prevents the Impairment of Cardiac Insulin Signaling and the Cardiac Pathogenesis in High-Fat Diet-Induced Obese Mice

Zhiguo Zhang1, 2, 3, Jing Chen3, Shanshan Zhou1, 2, 3, Shudong Wang1, 2, 3, Xiaohong Cai2, Daniel J. Conklin4, Ki-Soo Kim5, Ki Ho Kim6, Yi Tan2, 3, Yang Zheng1, ✉, Young Heui Kim7, ✉, Lu Cai2, 3

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
4. Diabetes and Obesity Center, University of Louisville, Louisville, KY 40202
5. Bioland Biotec HaiMen Co., Ltd, Linjiang New District, Haomen, 226100, China
6. KHBios, 505 Venture Center, 194-41, Osongsaengmyeong 1, Osong, Cheongju, Chungbuk 363-951, Republic of Korea
7. Bioland R&D Center, 59 Songjeongni 2-gil, Byeongcheon, Dongnam, Cheonan, Chungnam 330-863, Republic of Korea

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.

Keywords: Nrf2, obesity, lipid accumulation, lipotoxicity, cardiac insulin signaling, 4-O-methylhonokiol

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How to cite this article:
Zhang Z, Chen J, Zhou S, Wang S, Cai X, Conklin DJ, Kim KS, Kim KH, Tan Y, Zheng Y, Kim YH, Cai L. Magnolia Bioactive Constituent 4-O-Methylhonokiol Prevents the Impairment of Cardiac Insulin Signaling and the Cardiac Pathogenesis in High-Fat Diet-Induced Obese Mice. Int J Biol Sci 2015; 11(8):879-891. doi:10.7150/ijbs.12101. Available from http://www.ijbs.com/v11p0879.htm