Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil.
Clin Sci (Lond). 2010 Jun 8;119(6):239-50. doi: 10.1042/CS20100061.
The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action.
本研究旨在评估单药治疗和药物联合治疗对喂食高脂肪酸（HF）饮食的 C57BL/6 小鼠胰岛素敏感性、脂肪组织形态以及胰腺和肝脏重构的影响。雄性 C57BL/6 小鼠喂食 HF（60%脂质）饮食或 SC（标准饲料；10%脂质）饮食 10 周，此后开始以下药物治疗：HF-T（HF 饮食用替米沙坦治疗；5.2 mg x kg-1 的体重 x 天-1）、HF-S（HF 饮食用西他列汀治疗；1.08 g x kg-1 的体重 x 天-1）、HF-M（HF 饮食用二甲双胍治疗；310.0 mg x kg-1 的体重 x 天-1）、HF-TM（HF 饮食用替米沙坦+二甲双胍治疗）、HF-TS（HF 饮食用替米沙坦+西他列汀治疗）和 HF-SM（HF 饮食用西他列汀+二甲双胍治疗）。治疗组还可自由摄入 HF 饮食，治疗持续 6 周。采用形态计量学、立体学工具、免疫染色、ELISA、Western blot 分析和电子显微镜检查。HF 饮食导致超重表型、口服葡萄糖耐量受损、高胰岛素血症、胰岛和脂肪细胞肥大、2 期脂肪变性（>33%）以及肝脏过氧化物酶体增殖物激活受体-α（PPAR-α）和葡萄糖转运蛋白-2（GLUT-2）水平降低，同时固醇调节元件结合蛋白-1（SREBP-1）表达增强（P<0.0001）。相反，所有药物治疗均导致显著体重减轻、胰岛素抵抗逆转、胰岛和脂肪细胞肥大以及肝脂肪变性缓解。只有 HF-T 和 HF-TS 组在实验结束时体重与 SC 组相似，后一种治疗逆转了肝脂肪变性。PPAR-α 免疫染色增加，同时 GLUT-2 增加和 SREBP-1 表达降低，这可能解释了有利的肝脏结果。脂肪细胞大小的恢复与药物治疗组中更高的脂联素水平和更低的肿瘤坏死因子-α（TNF-α）水平（P<0.0001）一致。总之，所有药物治疗均有效控制代谢综合征。替米沙坦和西他列汀作为单药或双重治疗的效果最好，在肝脏中联合部分过氧化物酶体增殖物激活受体-γ激动剂和过氧化物酶体增殖物激活受体-α激活作用以及延长肠促胰岛素作用。
