Fletcher Justin A, Linden Melissa A, Sheldon Ryan D, Meers Grace M, Morris E Matthew, Butterfield Anthony, Perfield James W, Thyfault John P, Rector R Scott
Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
Department of Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
Am J Physiol Gastrointest Liver Physiol. 2016 May 15;310(10):G832-43. doi: 10.1152/ajpgi.00355.2015. Epub 2016 Mar 24.
Exercise stimulates hepatic mitochondrial adaptations; however, the mechanisms remain largely unknown. Here we tested whether FGF21 plays an obligatory role in exercise induced hepatic mitochondrial adaptations by testing exercise responses in FGF21 knockout mice. FGF21 knockout (FGF21-KO) and wild-type (WT) mice (11-12 wk of age) had access to voluntary running wheels for exercise (EX) or remained sedentary for 8 wk. FGF21 deficiency resulted in greater body weight, adiposity, serum cholesterol, insulin, and glucose concentrations compared with WT mice (P < 0.05). In addition, hepatic mitochondrial complete palmitate oxidation, β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity, and nuclear content of PGC-1α were 30-50% lower in FGF21-KO mice compared with WT mice (P < 0.01). EX effectively lowered body weight, adiposity, serum triglycerides, free fatty acids, and insulin and normalized mitochondrial complete palmitate oxidation in the FGF21-KO mice, whereas the reduced hepatic β-HAD activity and lowered nuclear content of PGC-1α in FGF21-KO mice were not restored by EX. In addition, EX increased hepatic CPT-1α mRNA expression and ACC phosphorylation (a marker of increased AMPK activity) and reduced hepatic triacylglycerol content in both genotypes. However, FGF21-KO mice displayed a lower EX-induced increase in the mRNA expression of the hepatic gluconeogenic gene, PEPCK, compared with WT. In conclusion, FGF21 does not appear necessary for exercise-induced systemic and hepatic mitochondrial adaptations, but the increased adiposity, hyperinsulinemia, and impairments in hepatic mitochondrial function induced by FGF21 deficiency can be partially rescued by daily wheel running exercise.
运动可刺激肝脏线粒体适应性变化；然而，其机制在很大程度上仍不清楚。在此，我们通过检测FGF21基因敲除小鼠的运动反应，来测试FGF21在运动诱导的肝脏线粒体适应性变化中是否起关键作用。FGF21基因敲除（FGF21-KO）小鼠和野生型（WT）小鼠（11-12周龄）可使用自愿跑步轮进行运动（EX），或连续8周保持 sedentary状态。与WT小鼠相比，FGF21缺乏导致体重、肥胖、血清胆固醇、胰岛素和葡萄糖浓度更高（P < 0.05）。此外，与WT小鼠相比，FGF21-KO小鼠肝脏线粒体中棕榈酸的完全氧化、β-羟酰基辅酶A脱氢酶（β-HAD）活性以及PGC-1α的核含量降低了30-50%（P < 0.01）。运动有效地降低了FGF21-KO小鼠的体重、肥胖、血清甘油三酯、游离脂肪酸和胰岛素水平，并使线粒体中棕榈酸的完全氧化恢复正常，而FGF21-KO小鼠肝脏中降低的β-HAD活性和降低的PGC-1α核含量并未通过运动恢复。此外，运动增加了两种基因型小鼠肝脏中CPT-1α mRNA表达和ACC磷酸化（AMPK活性增加的标志物），并降低了肝脏甘油三酯含量。然而，与WT小鼠相比，FGF21-KO小鼠肝脏糖异生基因PEPCK的mRNA表达在运动诱导下的增加较低。总之，FGF21似乎不是运动诱导的全身和肝脏线粒体适应性变化所必需的，但FGF21缺乏引起的肥胖增加、高胰岛素血症和肝脏线粒体功能损害可通过每日跑步运动得到部分改善。
