1654-P: Hepatic FGF21 Is Required for Curcumin and Resveratrol to Exert Their Metabolic Beneficial Effect in Male Mice

Abstract

Intensive investigations have shown the profound metabolic beneficial effect of dietary intervention with plant polyphenols including curcumin and resveratrol. Recent studies have also shown that hepatic FGF21 is among the targets of dietary polyphenol intervention as well as intermittent fasting or nutritional restriction. Here we assessed whether hepatic FGF21 is required for dietary polyphenol intervention on metabolic homeostasis in mice on high fat high fructose diet (HFHF) challenge. Liver specific FGF21 null mice (Lfgf21-/-) were generated by mating Alb-Cre mice with Fgf21fl/fl mice. No appreciable defect on glucose disposal was observed in male or female Lfgf21-/- mice when they were fed with regular chow diet. In chow diet fed male but not female Lfgf21-/- mice, fat tolerance was impaired, associated with elevated fasting plasma TG level and reduced hepatic expression of Ehhadh and Ppargc1 (two downstream targets of FGF21). Following HFHF challenge, the control Fgf21fl/fl male mice exhibited response to 12-week curcumin intervention on reducing body weight, serum and hepatic TG elevation, and on improving fat tolerance. Those beneficial effects were absent in male Lfgf21-/- mice. In high fat diet challenged wild type mice, concomitant resveratrol intervention exhibited anticipated metabolic beneficial effect, associated with increased hepatic FGF21 mRNA and protein expression. Importantly, the metabolic beneficial effects of resveratrol intervention were observed in HFHF challenged Fgf21fl/fl mice but not in Lfgf21-/- mice. In wild type or transgenic female mice, we did not see appreciable beneficial effect with resveratrol intervention. Together we introduced a transgenic mouse model into the investigation of metabolic function of dietary intervention. We conclude that hepatic FGF21 is required for curcumin or resveratrol to exert its beneficial effect in male mice. Disclosure W.Shao: None. J.Feng: None. T.Jin: None. Funding Canadian Institutes of Health Research