plants Communication Piceatannol Is Superior to Resveratrol at Suppressing Adipogenesis in Human Visceral Adipose-Derived Stem Cells In Sil Park 1, Youngjin Han 1 , HyunA Jo 1, Ki Won Lee 1,2,3,4,* and Yong Sang Song 1,5,* 1 Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea; [email protected] (I.S.P.); [email protected] (Y.H.); [email protected] (H.J.) 2 Advanced Institute of Convergence Technology, Seoul National University, Suwon 16229, Korea 3 Bio-MAX Institute, Seoul National University, Seoul 08826, Korea 4 Research & Development Center, BOBSNU Co., Ltd., Suwon 16229, Korea 5 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Korea * Correspondence: [email protected] (K.W.L.); [email protected] (Y.S.S.) Abstract: Resveratrol (3,40,5-trans-trihydroxystilbene) and piceatannol (3,30,40,5-trans-tetraphydroxy- stilbene) are major stilbene compounds that are predominantly present in various natural foods, such as berries and fruits. Both phytochemical compounds are consumed as dietary supplements to prevent various metabolic diseases and for their anti-aging properties. Adipose-derived stem cells from human visceral adipose tissue (vASCs) are a useful in vitro model for evaluating their adi- pogenic effect. Treatment with resveratrol and piceatannol significantly inhibited lipid accumulation in vASCs. Their effective concentrations were 5, 10, and 20 µM for inhibiting adipogenesis of vASCs. Interestingly, despite the similar chemical structures of the two compounds, piceatannol showed a higher anti-adipogenic effect at 20 µM than resveratrol in vASCs. Moreover, the inhibitory capacity µ of lipid droplet generation was higher for piceatannol at 20 M than that of resveratrol. Piceatannol significantly attenuated the expression level of adipogenic markers (e.g., CCAAT/enhanced binding α α γ γ Citation: Park, I.S.; Han, Y.; Jo, H.; protein (C/EBP ), peroxisome proliferator-activated receptor (PPAR ), and adipocyte fatty acid Lee, K.W.; Song, Y.S. Piceatannol Is binding protein (aP2)) compared to resveratrol at the mRNA and protein levels. These results suggest Superior to Resveratrol at that piceatannol is a superior anti-adipogenic compound compared to resveratrol in the vASC model Suppressing Adipogenesis in Human of visceral obesity. Visceral Adipose-Derived Stem Cells. Plants 2021, 10, 366. https://doi.org/ Keywords: resveratrol; piceatannol; obesity; adipogenesis; human visceral adipose-derived stem cells 10.3390/plants10020366 Academic Editor: Corina Danciu Received: 30 November 2020 1. Introduction Accepted: 9 February 2021 Resveratrol (3,40,5-trans-trihydroxystilbene, Res) and piceatannol (3,30,40,5-trans- tetra- Published: 14 February 2021 phydroxystilbene, Pic) are polyphenolic compounds. Res was first isolated in 1940 from the roots of white hellebore (Veratrum grandiflorum O. Loes) and the disease prevention effects Publisher’s Note: MDPI stays neutral of Res have since been extensively reported. Res has beneficial effects on many disease with regard to jurisdictional claims in types, such as neurological disorders [1], cardiovascular disease [2,3], and cancer [4,5]. published maps and institutional affil- iations. The identification and quantification of Pic were initially reported from the analysis of the domesticated oilseed, Euphorbia lagascae [6]. Although the health-promoting effects of Pic has been less extensively studied compared to Res, Pic has demonstrated cardiovascular disease prevention effects [7], anti-cancer effects [8,9], and anti-inflammatory activity [10]. Res and Pic are major stilbene compounds that are predominantly present in various Copyright: © 2021 by the authors. natural products, such as sim fruit (Rhodomyrtus tomentosa) seeds [11] and passion fruit Licensee MDPI, Basel, Switzerland. (Passiflora edulis) seeds [12]. The molecular structure of Res comprises two aromatic rings This article is an open access article connected by a methylene double bond. The chemical structures of Res and Pic are shown distributed under the terms and 0 conditions of the Creative Commons in Figure1a,b. Res and Pic have similar chemical structures, but Pic is a 3 hydroxylated Attribution (CC BY) license (https:// analog of Res (Figure1a,b). Owing to the similarity in chemical structure, both Res and creativecommons.org/licenses/by/ Pic possess similar biological activities, including antioxidants [13], decreasing tumor cell 4.0/). survival in colon cancer [14], and neuroprotective activity [15]. Plants 2021, 10, 366. https://doi.org/10.3390/plants10020366 https://www.mdpi.com/journal/plants Plants 2021, 10, x FOR PEER REVIEW 2 of 12 connected by a methylene double bond. The chemical structures of Res and Pic are shown in Figure 1a,b. Res and Pic have similar chemical structures, but Pic is a 3′hydroxylated analog of Res (Figure 1a,b). Owing to the similarity in chemical structure, both Res and Plants 2021, 10, 366 Pic possess similar biological activities, including antioxidants [13], decreasing tumor cell 2 of 12 survival in colon cancer [14], and neuroprotective activity [15]. OH OH HO HO OH OH OH (a) (b) FigureFigure 1. The 1.chemicalThe chemical structure structure of (a) ofresveratrol (a) resveratrol (Res) and (Res) (b) and piceat (b) piceatannolannol (Pic). In (Pic). the Instructure the structure formulaformula of Res, of two Res, aromatic two aromatic rings are rings connected are connected by one by methylene one methylene double double bond. bond.Pic is a Pic hydroxyl is a hydroxyl derivativederivative of Res. of Res. AmongAmong the various the various disorders, disorders, the prevalence the prevalence of obesity of obesity tripled tripled from 1975 from to 1975 2016. to 2016. AccordingAccording to the to World the World Health Health Organization Organization (WHO), (WHO), 39% of 39% adults of adults are overweight are overweight or or obese,obese, thereby thereby implying implying that obesity that obesity is beco isming becoming a pandemic a pandemic [16]. [ 16Obesity]. Obesity is considered is considered a a significantsignificant risk risk factor factor for for cardiovascular cardiovascular disease, disease, diabetes, diabetes, and and cancer leadingleading toto increased in- creasedmortality mortality worldwide worldwide [17 [1,187,18].]. Obesity Obesity originates originates from from excessive excessive lipidlipid accumulationaccumula- in tion inadipose adipose tissue. tissue. An An increase increase in in adipose adipos tissuee tissue proportions proportions is characterizedis characterized by anby increasean increasein adipocytein adipocyte cell cell number number and and size. size. Adipocytes Adipocytes are are derived derived fromfrom mesenchymalmesenchymal stem stem cells [19,20]. [19,20]. Adipogenesis Adipogenesis is is tightly tightly regulated regulated by by key key adipogenic adipogenic transcription transcription fac- factors, tors, includingincluding the the members of CCAAT/enhancedCCAAT/enhanced binding binding protein protein (C/EBP) (C/EBP) and and peroxi- peroxisome proliferator-activated receptor γ (PPARγ). Members of the C/EBP family include C/EBPα, some proliferator-activated receptor γ (PPARγ). Members of the C/EBP family include C/EBPβ, and C/EBPγ. Among them, C/EBPα is mainly involved in the cell fate during C/EBPα, C/EBPβ, and C/EBPγ. Among them, C/EBPα is mainly involved in the cell fate adipocyte differentiation. In addition, PPARγ is required for adipocyte differentiation during adipocyte differentiation. In addition, PPARγ is required for adipocyte differenti- and maintenance of mature adipocytes. Furthermore, the expression of adipocyte fatty ation and maintenance of mature adipocytes. Furthermore, the expression of adipocyte acid binding protein 2 (aP2) is altered during adipogenesis [21]. To identify natural food fatty acid binding protein 2 (aP2) is altered during adipogenesis [21]. To identify natural compounds that can efficiently prevent obesity, various natural compounds have been food compounds that can efficiently prevent obesity, various natural compounds have investigated for their anti-adipogenic effects. been investigated for their anti-adipogenic effects. In terms of the adipogenic effects of Res and Pic, anti-adipogenic effects have been In terms of the adipogenic effects of Res and Pic, anti-adipogenic effects have been observed in various in vitro models. Treatment with Res inhibits the maturation of 3T3-L1 observed in various in vitro models. Treatment with Res inhibits the maturation of 3T3- cells through the modulation of the insulin signaling pathways present in the murine L1 cellspreadipocyte through the cell modulation line 3T3-L1 of [the22, 23insuli]. Picn signaling inhibits the pathways early phase present of differentiation in the murine from preadipocyte3T3-L1 tocell adipocytes line 3T3-L1 by regulating[22,23]. Pic the inhi mitoticbits the clonal early expansion phase of differentiation and insulin signaling from [24]. 3T3-L1Moreover, to adipocytes a similar by regulating anti-adipogenic the mitoti effectc clonal occurs expansion in adipose-derived and insulin signaling stem cells [24]. (ASCs) Moreover,from humana similar subcutaneous anti-adipogenic adipose effect tissue occurs (sASCs) in adipose-derived [25]. Although stem previous cells studies(ASCs) have from utilizedhuman subcutaneous these cell lines adipose and sASCs tissue as useful (sASCs) models [25]. forAlthough studying previous the anti-adipogenic studies have effects utilizedof Resthese and