Biphasic Effects of Resveratrol on Adipogenesis: Low Doses of Resveratrol Promote Adipogenesis via Induction of CD36

Resveratrol (trans-3,4',-5-trihydroxystilebene), a calorie restriction mimetic, exerts anti-aging, anti-oxidative and immunomodulatory activities. However, both aging and resveratrol have been shown to inhibit the differentiation of preadipocytes. Since relatively high doses of resveratrol were employed previously, we reexamined the dosedependent effects of resveratrol on 3T3-L1 preadipocyte differentiation. Although 40 mM resveratrol inhibited adipogenesis, low doses (10-20 mM) promoted the differentiation of 3T3-L1 cells as evidenced by the enhanced levels of glycerol-3-phosphate dehydrogenase (GPDH) activity and lipid droplet accumulation, and by the increased mRNA expression of mature adipocyte markers such as adipocyte fatty acidbinding protein (aP2) and adiponectin. Resveratrol (15 mM) treatment enhanced protein levels of C/EBPγ, C/EBPα and PPARg which are master transcription factors governing adipocyte differentiation. Furthermore, 15 mM resveratrol induced CD36, an adipogenesis promoter, whereas 35 mM resveratrol repressed it during adipogenesis. Moreover, CD36 neutralizing antibodies attenuated the promoting effect of 15 mM resveratrol on adipogenesis. Resveratrol at 35 mM, but not 15 mM, up-regulated HO-1, a known adipogenesis inhibitor. These results suggest that CD36 and HO-1 at least partly mediate biphasic effects of resveratrol on adipogenesis, and that low doses of resveratrol enhance adipogenesis of 3T3-L1 cells by up-regulating CD36, whereas high doses of resveratrol inhibit adipogenesis by reducing CD36 and elevating HO-1.