Linden Melissa A, Fletcher Justin A, Meers Grace M, Thyfault John P, Laughlin M Harold, Rector R Scott
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri;
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri;
Am J Physiol Gastrointest Liver Physiol. 2016 Sep 1;311(3):G387-95. doi: 10.1152/ajpgi.00089.2016. Epub 2016 Jul 21.
Hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats develop obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD), but lifestyle modifications, such as caloric restriction (CR), can prevent these conditions. We sought to determine if prior CR had protective effects on metabolic health and NAFLD development following a 4-wk return to ad libitum (AL) feeding. Four-week-old male OLETF rats (n = 8-10/group) were fed AL for 16 wk (O-AL), CR for 16 wk (O-CR; ∼70% kcal of O-AL), or CR for 12 wk followed by 4 wk of AL feeding (O-AL4wk). CR-induced benefit in prevention of NAFLD, including reduced hepatic steatosis, inflammation, and markers of Kupffer cell activation/number, was largely lost in AL4wk rats. These findings occurred in conjunction with a partial loss of CR-induced beneficial effects on obesity and serum triglycerides in O-AL4wk rats, but in the absence of changes in serum glucose or insulin. CR-induced increases in hepatic mitochondrial respiration remained significantly elevated (P < 0.01) in O-AL4wk compared with O-AL rats, while mitochondrial [1-(14)C]palmitate oxidation, citrate synthase activity, and β-hydroxyacyl-CoA dehydrogenase activity did not differ among OLETF groups. NAFLD development in O-AL4wk rats was accompanied by increases in the protein content of the de novo lipogenesis markers fatty acid synthase and stearoyl-CoA desaturase-1 and decreases in phosphorylated acetyl-CoA carboxylase (pACC)/ACC compared with O-CR rats (P < 0.05 for each). The beneficial effects of chronic CR on NAFLD development were largely lost with 4 wk of AL feeding in the hyperphagic OLETF rat, highlighting the importance of maintaining energy balance in the prevention of NAFLD.
食欲亢进的大冢长-艾氏-德岛肥胖（OLETF）大鼠会出现肥胖、胰岛素抵抗和非酒精性脂肪性肝病（NAFLD），但生活方式的改变，如热量限制（CR），可以预防这些情况。我们试图确定先前的热量限制对恢复自由采食（AL）4周后的代谢健康和NAFLD发展是否具有保护作用。将4周龄的雄性OLETF大鼠（每组n = 8 - 10只）自由采食16周（O-AL），热量限制16周（O-CR；约为O-AL组热量的70%），或热量限制12周后再自由采食4周（O-AL4wk）。热量限制对NAFLD的预防益处，包括肝脂肪变性、炎症以及库普弗细胞活化/数量标志物的减少，在O-AL4wk大鼠中基本丧失。这些发现伴随着O-AL4wk大鼠中热量限制对肥胖和血清甘油三酯的有益作用部分丧失，但血清葡萄糖或胰岛素没有变化。与O-AL大鼠相比，O-AL4wk大鼠中热量限制引起的肝线粒体呼吸增加仍显著升高（P < 0.01），而线粒体[1-(14)C]棕榈酸氧化、柠檬酸合酶活性和β-羟酰基辅酶A脱氢酶活性在OLETF各组之间没有差异。与O-CR大鼠相比，O-AL4wk大鼠中NAFLD的发展伴随着从头脂肪生成标志物脂肪酸合酶和硬脂酰辅酶A去饱和酶-1的蛋白质含量增加，以及磷酸化乙酰辅酶A羧化酶（pACC）/ACC的减少（每组P < 0.05）。在食欲亢进的OLETF大鼠中，自由采食4周后，慢性热量限制对NAFLD发展的有益作用基本丧失，这突出了维持能量平衡在预防NAFLD中的重要性。
