Feng Jia Nuo, Shao Weijuan, Yang Lin, Pang Juan, Ling Wenhua, Liu Dinghui, Wheeler Michael B, He Housheng Hansen, Jin Tianru
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Nutr Diabetes. 2025 Feb 10;15(1):4. doi: 10.1038/s41387-025-00363-0.
Our mechanistic understanding on metabolic beneficial effects of dietary polyphenols has been hampered for decades due to the lack of functional receptors for those compounds and their extremely low plasma concentrations. Recent studies by our team and others suggest that those dietary polyphenols target gut microbiome, and gut-liver axis and that hepatic fibroblast factor 21 (FGF21) serves as a common target for various dietary interventions.
Utilizing liver-specific FGF21 null mice (lFgf21), we are asking a straightforward question: Is hepatic FGF21 required for curcumin or resveratrol, two typical dietary polyphenols, in exerting their metabolic beneficial effect in obesogenic diet-induced obesity mouse models.
On low-fat diet feeding, no appreciable defect on glucose disposal was observed in male or female lFgf21 mice, while fat tolerance was moderately impaired in male but not in female lFgf21 mice, associated with elevated random and fasting serum triglyceride (TG) levels, and reduced hepatic expression of Ehhadh and Ppargc1a, which encodes the two downstream effectors of FGF21. On high-fat-high-fructose (HFHF) diet challenge, Fgf21 but not lFgf21 mice exhibited response to curcumin intervention on reducing fasting serum TG, and on improving fat tolerance. Resveratrol intervention also affected FGF21 expression or its downstream effectors. Metabolic beneficial effects of resveratrol intervention observed in HFHF diet-challenged Fgf21 mice were either absent or attenuated in lFgf21 mice.
We conclude that hepatic FGF21 is required for curcumin or resveratrol in exerting their major metabolic beneficial effect. The recognition that FGF21 as the common target of dietary intervention, demonstrated in current as well as previous investigations, brings us a novel angle in understanding metabolic disease treatment and prevention. It remains to be further explored how various dietary interventions regulate FGF21 expression and function, via certain common or unique gut-liver or gut-brain-liver axis.
由于缺乏膳食多酚类化合物的功能性受体以及它们在血浆中的浓度极低，数十年来我们对膳食多酚代谢有益作用的机制理解一直受到阻碍。我们团队和其他团队最近的研究表明，这些膳食多酚靶向肠道微生物群以及肠 - 肝轴，并且肝脏成纤维细胞生长因子21（FGF21）是各种膳食干预的共同靶点。
利用肝脏特异性FGF21基因敲除小鼠（lFgf21），我们提出一个简单的问题：在致肥胖饮食诱导的肥胖小鼠模型中，姜黄素或白藜芦醇这两种典型的膳食多酚发挥其代谢有益作用时，肝脏FGF21是否是必需的？
在低脂饮食喂养下，雄性或雌性lFgf21小鼠在葡萄糖处理方面未观察到明显缺陷，而雄性lFgf21小鼠的脂肪耐受性中度受损，雌性则未受损，这与随机和空腹血清甘油三酯（TG）水平升高以及肝脏中编码FGF21两个下游效应器的Ehhadh和Ppargc1a表达降低有关。在高脂高果糖（HFHF）饮食挑战下，Fgf21小鼠而非lFgf21小鼠对姜黄素干预表现出降低空腹血清TG以及改善脂肪耐受性的反应。白藜芦醇干预也影响FGF21表达或其下游效应器。在HFHF饮食挑战的Fgf21小鼠中观察到的白藜芦醇干预的代谢有益作用在lFgf21小鼠中不存在或减弱。
我们得出结论，姜黄素或白藜芦醇发挥其主要代谢有益作用需要肝脏FGF21。当前以及先前研究表明FGF21是膳食干预的共同靶点，这为我们理解代谢性疾病的治疗和预防带来了一个新的视角。各种膳食干预如何通过某些共同或独特的肠 - 肝或肠 - 脑 - 肝轴调节FGF21的表达和功能仍有待进一步探索。
