5,4′-Dihydroxy-7,8-dimethoxyflavanone and Aliarin from Dodonaea viscosa Are Activators of PPARγ

Jing-Jie Zhu; Jun Ji; Ai-Jun Hou; He-Yao Wang

doi:10.1055/s-0043-120270

Planta Medica, Table of Contents

Planta Med 2018; 84(08): 500-506
DOI: 10.1055/s-0043-120270

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

5,4′-Dihydroxy-7,8-dimethoxyflavanone and Aliarin from Dodonaea viscosa Are Activators of PPARγ

Authors

Jing-Jie Zhu

¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

³University of Chinese Academy of Sciences, Beijing, China
Jun Ji

²Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai, China
Ai-Jun Hou

²Department of Pharmacognosy, School of Pharmacy, Fudan University, Shanghai, China
He-Yao Wang

¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Abstract

PPARγ agonists are widely used medications in diabetes mellitus therapy. Their role in improving adipose tissue function contributes to antidiabetic effects. The extracts of Dodonaea viscosa have been reported to exert antidiabetic activity. However, the effective mediators and the underlying mechanisms were largely unknown. In this study, we investigated the action on PPARγ transactivation and adipocyte modulation of two typical flavonoid constituents from D. viscosa, 5,4′-dihydroxy-7,8-dimethoxyflavanone and aliarin. Our results showed that 5,4′-dihydroxy-7,8-dimethoxyflavanone and aliarin were potential partial PPARγ agonists. The compounds induced adipogenesis in 3T3-L1 cells, with an upregulated adiponectin mRNA level and enhanced insulin sensitivity. The favorable effects of 5,4′-dihydroxy-7,8-dimethoxyflavanone, aliarin, and other flavonoid constituents on adipocytes might contribute to the antidiabetic efficacy of D. viscosa.

Key words

Dodonaea viscosa - Sapindaceae - 5,4′-dihydroxy-7,8-dimethoxyflavanone - aliarin - diabetes mellitus - adipogenesis - partial PPARγ agonists

Full Text

References

References
1 Hallenborg P, Petersen RK, Kouskoumvekaki I, Newman JW, Madsen L, Kristiansen K. The elusive endogenous adipogenic PPARγ agonists: lining up the suspects. Prog Lipid Res 2015; 61: 149-162
2 Rangwala SM, Lazar MA. Peroxisome proliferator-activated receptor γ in diabetes and metabolism. Trends Pharmacol Sci 2004; 25: 331-336
3 Balkau B, Deanfield JE, Despres JP, Bassand JP, Fox KA, Smith jr. SC, Barter P, Tan CE, Van Gaal L, Wittchen HU, Massien C, Haffner SM. International day for the evaluation of abdominal obesity (IDEA): a study of waist circumference, cardiovascular disease, and diabetes mellitus in 168,000 primary care patients in 63 countries. Circulation 2007; 116: 1942-1951
4 Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, Stumvoll M, Bluher M. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010; 299: E506-E515
5 Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010; 11: 11-18
6 Laurencikiene J, Skurk T, Kulyte A, Heden P, Astrom G, Sjolin E, Ryden M, Hauner H, Arner P. Regulation of lipolysis in small and large fat cells of the same subject. J Clin Endocrinol Metab 2011; 96: E2045-E2049
7 Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. The correlation between adiposity and adiponectin, tumor necrosis factor α, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults?. J Endocrinol Invest 2007; 30: 210-214
8 Bays HE, Gonzalez-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, Rodbard HW, Henry RR. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther 2008; 6: 343-368
9 Campbell IW. The clinical significance of PPARγ agonism. Curr Mol Med 2005; 5: 349-363
10 Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7: 885-896
11 Lefterova MI, Lazar MA. New developments in adipogenesis. Trends Endocrinol Metab 2009; 20: 107-114
12 Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab 2007; 5: 237-252
13 Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008; 7: 489-503
14 Andrade-Oliveira V, Camara NO, Moraes-Vieira PM. Adipokines as drug targets in diabetes and underlying disturbances. J Diabetes Res 2015; 2015: 681612
15 Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM, Wade MR, Tenorio VM, Kuo MS, Brozinick JT, Zhang BB, Birnbaum MJ, Summers SA, Scherer PE. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 2011; 17: 55-63
16 Zhang LB, Ji J, Lei C, Wang HY, Zhao QS, Hou AJ. Isoprenylated flavonoid and adipogenesis-promoting constituents of Dodonaea viscosa . J Nat Prod 2012; 75: 699-706
17 Veerapur VP, Prabhakar KR, Thippeswamy BS, Bansal P, Srinivasan KK, Unnikrishnan MK. Antidiabetic effect of Dodonaea viscosa (L). Lacq. aerial parts in high fructose-fed insulin resistant rats: a mechanism based study. Indian J Exp Biol 2010; 48: 800-810
18 Veerapur VP, Prabhakar KR, Kandadi MR, Srinivasan KK, Unnikrishnan MK. Antidiabetic effect of Dodonaea viscosa aerial parts in high fat diet and low dose streptozotocin-induced type 2 diabetic rats: a mechanistic approach. Pharm Biol 2010; 48: 1137-1148
19 Song Y, Kim MB, Kim C, Kim J, Hwang JK. 5, 7-Dimethoxyflavone attenuates obesity by inhibiting adipogenesis in 3T3-L1 adipocytes and high-fat diet-induced obese C57BL/6J mice. J Med Food 2016; 19: 1111-1119
20 Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998; 395: 137-143
21 Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He Y, Nettles KW, Griffin PR. Partial agonists activate PPARγ using a helix 12 independent mechanism. Structure 2007; 15: 1258-1271
22 El-Houri RB, Mortier J, Murgueitio MS, Wolber G, Christensen LP. Identification of PPARγ agonists from natural sources using different in silico approaches. Planta Med 2015; 81: 488-494
23 Hughes TS, Chalmers MJ, Novick S, Kuruvilla DS, Chang MR, Kamenecka TM, Rance M, Johnson BA, Burris TP, Griffin PR, Kojetin DJ. Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism. Structure 2012; 20: 139-150
24 DeFronzo RA. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int J Clin Pract Suppl 2004; 143: 9-21
25 Min BS, Ahn BZ, Bae KH. Synthesis and structure-activity relationship of cytotoxic 5,2′,5′-trihydroxy-7,8-dimethoxyflavanone analogues. Arch Pharm Res 1996; 19: 543-550
26 Sachdev K, Kulshreshtha DK. Aliarin, a new flavonoid from Dodonaea viscosa Linn. Indian J Chem Section B 1982; 21: 798-799
27 Ji J, Zhu J, Hu X, Wang T, Zhang X, Hou AJ, Wang H. (2S)-7,4′-dihydroxy-8-prenylflavan stimulates adipogenesis and glucose uptake through p38MAPK pathway in 3T3-L1 cells. Biochem Biophys Res Commun 2015; 460: 578-582
28 Zhu JJ, Huang JS, Wang T, Ji J, Hou AJ, Wang HY. Sanggenol F exerts anti-diabetic effects via promoting adipocyte differentiation and modifying adipokines expression. Endocrine 2017; 56: 73-81
29 Zhu JJ, Yan GR, Xu ZJ, Hu X, Wang GH, Wang T, Zhu WL, Hou AJ, Wang HY. Inhibitory effects of (2′R)-2′,3′-dihydro-2′-(1-hydroxy-1-methylethyl)-2,6′-bibenzofuran-6,4′-diol on mushroom tyrosinase and melanogenesis in B16–F10 melanoma cells. Phytother Res 2015; 29: 1040-1045