Power Guerra Nicole, Leyens Katharina, Müller Luisa, Brauer David, Janowitz Deborah, Schlick Samin, Pilz Kristin, Grabe Hans J, Vollmar Brigitte, Kuhla Angela
Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
Institute of Anatomy, Rostock University Medical Center, Rostock, Germany.
Front Nutr. 2022 Aug 10;9:935805. doi: 10.3389/fnut.2022.935805. eCollection 2022.
Obesity, often associated with non-alcoholic fatty liver disease (NAFLD), is characterized by an imbalance between energy expenditure and food intake, which is also reflected by desensitization of fibroblast growth factor 21 (FGF21). FGF21 is strongly influenced, among others, by TNFα, which is known to be upregulated in obesity-induced inflammation. Successful long-term treatments of NAFLD might be dietary modification, exercise, or fasting.
Whether succeeded NAFLD recovery is linked with improved FGF21 sensitivity and finally reverted FGF21 resistance was the focus of the present study. For this purpose, mice received a high-fat diet (HFD) for 6 months to establish obesity. Afterward, the mice were subjected to three different weight loss interventions, namely, dietary change to low-fat diet (LFD), treadmill training, and/or time-restricted feeding for additional 6 months, whereas one group remained on HFD.
In addition to the expected decrease in NAFLD activity with dietary change, this was also observed in the HFD group with additional time-restricted feeding. There was also an associated decrease in hepatic TNFα and FGF21 expression and an increase in ß-klotho expression, demonstrated mainly by using principal component analysis. Pearson correlation analysis shows that independent of any intervention, TNFα expression decreased with improved NAFLD recovery. This was accompanied with higher FGF21 sensitivity, as expressed by an increase in β-klotho and FGFR1c expression and concomitantly decreased FGF21 levels.
In summary, we conclude that successful NAFLD therapy is associated with a reversion of the TNFα-triggered FGF21-resistant state or desensitization.
肥胖常与非酒精性脂肪性肝病（NAFLD）相关，其特征在于能量消耗与食物摄入之间的失衡，这也通过成纤维细胞生长因子21（FGF21）的脱敏反映出来。FGF21受到多种因素的强烈影响，其中TNFα已知在肥胖诱导的炎症中上调。NAFLD的成功长期治疗可能是饮食调整、运动或禁食。
本研究的重点是NAFLD的成功恢复是否与FGF21敏感性的改善以及最终FGF21抵抗的逆转有关。为此，小鼠接受高脂肪饮食（HFD）6个月以建立肥胖模型。之后，小鼠接受三种不同的体重减轻干预措施，即改为低脂饮食（LFD）、跑步机训练和/或限时喂养，持续6个月，而一组继续给予HFD。
除了饮食改变导致NAFLD活动预期下降外，在HFD组中额外进行限时喂养也观察到了这一点。还观察到肝脏TNFα和FGF21表达降低以及β-klotho表达增加，主要通过主成分分析证实。Pearson相关分析表明，独立于任何干预措施，TNFα表达随着NAFLD恢复的改善而降低。这伴随着更高的FGF21敏感性，表现为β-klotho和FGFR1c表达增加以及FGF21水平相应降低。
总之，我们得出结论，成功的NAFLD治疗与TNFα触发的FGF21抵抗状态的逆转或脱敏有关。
