Uchinaka Ayako, Yoneda Mamoru, Yamada Yuichiro, Murohara Toyoaki, Nagata Kohzo
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Pharmacol Res Perspect. 2017 Aug;5(4). doi: 10.1002/prp2.331.
The mammalian target of rapamycin (mTOR) is a regulator of metabolism and is implicated in pathological conditions such as obesity and diabetes. We aimed to investigate the role of mTOR in obesity. A new animal model of metabolic syndrome (MetS), named DahlS.Z-Lepr /Lepr (DS/obese) rats was established previously in our laboratory. In this study, we used this model to evaluate the effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism. DS/obese rats were treated with the mTOR inhibitor, everolimus, (0.83 mg/kg per day, per os) for 4 weeks at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr /Lepr or DS/lean) littermates of DS/obese rats were used as controls. Treatment with everolimus ameliorated hypertension, left ventricular (LV) hypertrophy and fibrosis, and LV diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats, but had no effect on these parameters in DS/lean rats. Treatment with everolimus reduced Akt Thr308 phosphorylation in the heart of DS/obese rats. It also alleviated obesity, hyperphagia, adipocyte hypertrophy, and adipose tissue inflammation in DS/obese rats. Everolimus treatment exacerbated glucose intolerance, but did not affect Akt phosphorylation levels in the fat or liver in these rats. Pancreatic β-cell mass was increased in DS/obese rats compared with that in DS/lean rats and this effect was attenuated by everolimus. Activation of mTOR signaling contributes to the pathophysiology of MetS and its associated complications. And mTOR inhibition with everolimus ameliorated obesity as well as cardiac and adipose tissue pathology, but exacerbated glucose metabolism in rats with MetS.
雷帕霉素的哺乳动物靶点（mTOR）是一种代谢调节因子，与肥胖和糖尿病等病理状况有关。我们旨在研究mTOR在肥胖中的作用。我们实验室先前建立了一种名为DahlS.Z-Lepr/Lepr（DS/肥胖）大鼠的新型代谢综合征（MetS）动物模型。在本研究中，我们使用该模型评估mTOR抑制对心脏和脂肪组织病理以及葡萄糖代谢的影响。DS/肥胖大鼠在9周龄时接受mTOR抑制剂依维莫司（每天0.83毫克/千克，口服）治疗4周。将年龄匹配的DS/肥胖大鼠的纯合瘦型（DahlS.Z-Lepr/Lepr或DS/瘦）同窝仔鼠用作对照。依维莫司治疗改善了DS/肥胖大鼠的高血压、左心室（LV）肥厚和纤维化以及LV舒张功能障碍，并减轻了心脏氧化应激和炎症，但对DS/瘦大鼠的这些参数没有影响。依维莫司治疗降低了DS/肥胖大鼠心脏中Akt Thr308的磷酸化水平。它还减轻了DS/肥胖大鼠的肥胖、食欲亢进、脂肪细胞肥大和脂肪组织炎症。依维莫司治疗加剧了葡萄糖不耐受，但不影响这些大鼠脂肪或肝脏中的Akt磷酸化水平。与DS/瘦大鼠相比，DS/肥胖大鼠的胰腺β细胞质量增加，依维莫司减弱了这种作用。mTOR信号通路的激活促成了MetS及其相关并发症的病理生理学。依维莫司抑制mTOR改善了肥胖以及心脏和脂肪组织病理，但加剧了MetS大鼠的葡萄糖代谢。
