(PTFS03-01-25) Resveratrol Intervention Exerts Beneficial Metabolic Effects in High Fat Diet-Challenged Middle-Aged Female Mice Involving Hepatic FGF21

Objectives: Over past 2-3 decades, beneficial effects of dietary polyphenols (DPs) have been intensively studied. Among them, resveratrol (REV) intervention (REV-I) has been demonstrated to exert metabolic effects such as attenuating hyperglycemia, promoting insulin secretion and improving insulin sensitivity, making it a promising nutritional supplementation or preventative agent for type 2 diabetes (T2D). Previous investigations led by our team and others have shown that DPs target hepatic hormone, fibroblast growth factor 21 (FGF21). Studies also revealed that REV serves as mixed agonist and antagonist of estrogen receptors. We hence investigated whether REV-I exerts beneficial metabolic effects and targets hepatic FGF21 in middle-aged female mice under metabolic challenge.

Methods: Here, we utilized 36-week-old C57BL/6J female mice to investigate whether REV-I exert metabolic benefits under high fat diet (HFD) challenge. Mice were randomly assigned to receive normal chow diet, HFD (60% fat) or HFD with REV-I (0.5% of the diet) for 18 weeks.

Results: In middle-aged female mice with HFD challenge, 18-week of concomitant REV-I attenuated body weight gain, reduced epidydimal and inguinal white adipose tissue (eWAT and iWAT, respectively) weights and improved insulin sensitivity compared to mice on HFD alone. In liver, REV-I had no effect on gluconeogenic process yet significantly attenuated a battery of genes that are involved in lipogenesis. In addition, concomitant REV-I also restored HFD-induced attenuation on plasma FGF21 and improved FGF21 sensitivity in eWAT. HFD feeding also significantly repressed fatty acid beta oxidation gene Pdk4, and such alteration were partially restored by REV-I. In ileum, nor did HFD or REV-I exert effects on maintaining bile acid and lipid homeostasis suggesting that female mice might be partially protected against HFD-induced metabolic impairments.

Conclusions: Together, our investigation elucidates the metabolic roles of REV-I in middle-aged female mice under HFD-challenge. Collectively, we suggest that REV-I attenuates HFD-induced body weight gain, improves insulin sensitivity and regulates fatty acid metabolism. REV-I also stimulates plasma FGF21 and improves FGF21 sensitivity in eWAT in this female mouse model.

Funding Sources: This study is supported by Canadian Institutes of Health Research (PJT159735).