Moore G B T, Pickavance L C, Briscoe C P, Clapham J C, Buckingham R E, Wilding J P H
Department of Vascular Biology, GlaxoSmithKline, New Frontiers Science Park North, Harlow, Essex, UK.
Diabetes Obes Metab. 2008 Mar;10(3):251-63. doi: 10.1111/j.1463-1326.2007.00697.x.
Consumption of a palatable diet can induce hyperphagia, leading to weight gain (dietary obesity) and insulin resistance in rats. Thiazolidinediones (TZDs) can also induce hyperphagia in rats but conversely have an insulin-sensitizing effect. The aim of this study was to investigate whether preventing TZD-induced hyperphagia (i.e. energy restriction) in dietary obese (DIO) rats would enhance the insulin-sensitizing effects of treatment at a therapeutic dose; and, within this paradigm, to produce an original survey of candidate TZD-gene targets in the clinically relevant visceral white adipose tissue (WAT) depot.
DIO rats that were either freely fed or energy restricted (i.e. pair-fed to the level of untreated controls) were treated with rosiglitazone maleate (RSG; 3 mg/kg/day) for 2 weeks, the restricted group controlling for treatment-induced hyperphagia and weight gain. The outcome measures were circulating concentrations of various biochemical markers of insulin resistance, and gene expression was measured in epididymal WAT.
In both freely fed and pair-fed groups, compared to untreated DIO controls, RSG reduced plasma levels of insulin (-29% and -43%; p < 0.05 and p < 0.001, respectively), free fatty acids (FFAs; -45% and -48%; p < 0.01 and p < 0.001, respectively) and triglycerides (TGs; -63% and -72%; both p < 0.001), reflected in improved insulin sensitivity, as measured by homeostasis model assessment (-29% and -43%; p < 0.01 and p < 0.0001). RSG also increased the expression of the fatty acid transport/synthesis genes, fatty acid transport protein (2.4-3.2-fold), epidermal fatty acid-binding protein (FABP; 1.7-2.0-fold), heart FABP (25-29-fold) and fatty acid synthase (2.3-2.9-fold; all p < 0.05) in both groups. Adipocyte FABP was also increased by RSG treatment, but only in combination with energy restriction (1.52-fold; p < 0.05) as was hexokinase II expression (p < 0.001). In contrast, the drug had no effect on expression of several genes associated with lipolysis. Although obesity-induced hyperleptinaemia was normalized only in the energy-restricted group, leptin messenger RNA (mRNA) expression was reduced in both treated groups (all p < 0.01). Resistin and tumour necrosis factor-alpha expression was also reduced, though in the latter case, only with energy restriction (p < 0.05). Other adipokines were unaffected by RSG treatment.
Our results clearly show that energy restriction enhances the therapeutic efficacy of TZDs and suggest that this occurs, at least in part, through a modulatory effect on gene expression in visceral WAT. These findings improve our understanding of the underlying mechanistic basis for the clinical usefulness of dietary restriction as an adjunct to TZD therapy in type 2 diabetes.
食用可口饮食可诱发大鼠食欲亢进，导致体重增加（饮食性肥胖）及胰岛素抵抗。噻唑烷二酮类药物（TZDs）也可诱发大鼠食欲亢进，但相反地具有胰岛素增敏作用。本研究的目的是调查在饮食性肥胖（DIO）大鼠中预防TZDs诱发的食欲亢进（即能量限制）是否会增强治疗剂量治疗的胰岛素增敏作用；并且，在此范式下，对临床相关的内脏白色脂肪组织（WAT）库中的候选TZDs基因靶点进行初步研究。
将自由进食或能量受限（即与未治疗对照的进食量配对）的DIO大鼠用马来酸罗格列酮（RSG；3mg/kg/天）治疗2周，受限组控制治疗诱发的食欲亢进和体重增加。观察指标为胰岛素抵抗的各种生化标志物的循环浓度，并在附睾WAT中测量基因表达。
在自由进食组和配对进食组中，与未治疗的DIO对照相比，RSG降低了血浆胰岛素水平（分别降低29%和43%；p<0.05和p<0.001）、游离脂肪酸（FFAs；分别降低45%和48%；p<0.01和p<0.001）和甘油三酯（TGs；分别降低63%和72%；均p<0.001），通过稳态模型评估测量显示胰岛素敏感性得到改善（分别降低29%和43%；p<0.01和p<0.0001）。RSG还增加了两组中脂肪酸转运/合成基因、脂肪酸转运蛋白（2.4 - 3.2倍）、表皮脂肪酸结合蛋白（FABP；1.7 - 2.0倍）、心脏FABP（25 - 29倍）和脂肪酸合酶（2.3 - 2.9倍；均p<0.05）的表达。RSG治疗也增加了脂肪细胞FABP的表达，但仅与能量限制联合时增加（1.52倍；p<0.05），己糖激酶II的表达也增加（p<0.001）。相比之下，该药物对与脂肪分解相关的几个基因的表达没有影响。尽管仅在能量受限组中肥胖诱导的高瘦素血症恢复正常，但两个治疗组中的瘦素信使核糖核酸（mRNA）表达均降低（均p<0.01）。抵抗素和肿瘤坏死因子-α的表达也降低，不过在后一种情况下，仅在能量限制时降低（p<0.05）。其他脂肪因子不受RSG治疗的影响。
我们的结果清楚地表明能量限制增强了TZDs的治疗效果，并表明这至少部分是通过对内脏WAT中基因表达的调节作用发生的。这些发现增进了我们对饮食限制作为2型糖尿病中TZDs治疗辅助手段临床有用性的潜在机制基础的理解。
