Fabris R, Nisoli E, Lombardi A M, Tonello C, Serra R, Granzotto M, Cusin I, Rohner-Jeanrenaud F, Federspil G, Carruba M O, Vettor R
Department of Medical and Surgical Sciences, University of Padova, Italy.
Diabetes. 2001 Mar;50(3):601-8. doi: 10.2337/diabetes.50.3.601.
The preferential channeling of different fuels to fat and changes in the transcription profile of adipose tissue and skeletal muscle are poorly understood processes involved in the pathogenesis of obesity and insulin resistance. Carbohydrate and lipid metabolism may play relevant roles in this context. Freely moving lean Zucker rats received 3- and 24-h infusions of Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, or saline plus heparin, to evaluate how an increase in free fatty acids (nonesterified fatty acid [NEFA]) modulates fat tissue and skeletal muscle gene expression and thus influences fuel partitioning. Glucose uptake was determined in various tissues at the end of the infusion period by means of the 2-deoxy-[1-3H]-D-glucose technique after a euglycemic-hyperinsulinemic clamp: high NEFA levels markedly decreased insulin-mediated glucose uptake in red fiber-type muscles but enhanced glucose utilization in visceral fat. Using reverse transcriptase-polymerase chain reaction and Northern blotting analyses, the mRNA expression of fatty acid translocase (FAT)/CD36, GLUT4, tumor necrosis factor (TNF)-alpha, peroxisome proliferator-activated receptor (PPAR)-gamma, leptin, uncoupling protein (UCP)-2, and UCP-3 was investigated in different fat depots and skeletal muscles before and after the study infusions. GLUT4 mRNA levels significantly decreased (by approximately 25%) in red fiber-type muscle (soleus) and increased (by approximately 45%) in visceral adipose tissue. Furthermore, there were marked increases in FAT/CD36, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 mRNA levels in the visceral fat and muscle of the treated animals in comparison with those measured in the saline-treated animals. These data suggest that the in vivo gene expression of FAT/CD36, GLUT4, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 in visceral fat and red fiber-type muscle are differently regulated by circulating lipids and that selective insulin resistance seems to favor, at least in part, a prevention of fat accumulation in tissues not primarily destined for fat storage, thus contributing to increased adiposity and the development of a prediabetic syndrome.
不同燃料优先流向脂肪以及脂肪组织和骨骼肌转录谱的变化，是肥胖症和胰岛素抵抗发病机制中尚未完全了解的过程。在此背景下，碳水化合物和脂质代谢可能发挥相关作用。自由活动的瘦型 Zucker 大鼠接受了 3 小时和 24 小时的英脱利匹特（意大利米兰法玛西亚普强公司生产）加肝素或生理盐水加肝素输注，以评估游离脂肪酸（非酯化脂肪酸 [NEFA]）增加如何调节脂肪组织和骨骼肌基因表达，进而影响燃料分配。在等血糖 - 高胰岛素钳夹后，通过 2 - 脱氧 - [1 - 3H] - D - 葡萄糖技术在输注期结束时测定各种组织中的葡萄糖摄取：高 NEFA 水平显著降低了红纤维型肌肉中胰岛素介导的葡萄糖摄取，但增强了内脏脂肪中的葡萄糖利用。使用逆转录酶 - 聚合酶链反应和 Northern 印迹分析，在研究输注前后，对不同脂肪储存部位和骨骼肌中脂肪酸转运蛋白（FAT）/CD36、葡萄糖转运蛋白 4（GLUT4）、肿瘤坏死因子（TNF） - α、过氧化物酶体增殖物激活受体（PPAR） - γ、瘦素、解偶联蛋白（UCP） - 2 和 UCP - 3 的 mRNA 表达进行了研究。GLUT4 mRNA 水平在红纤维型肌肉（比目鱼肌）中显著降低（约 25%），在内脏脂肪组织中升高（约 45%）。此外，与生理盐水处理的动物相比，处理动物的内脏脂肪和肌肉中 FAT/CD36、TNF - α、PPAR - γ、瘦素、UCP2 和 UCP3 的 mRNA 水平显著升高。这些数据表明，循环脂质对内脏脂肪和红纤维型肌肉中 FAT/CD36、GLUT4、TNF - α、PPAR - γ、瘦素、UCP2 和 UCP3 的体内基因表达有不同的调节作用，并且选择性胰岛素抵抗似乎至少部分有利于防止脂肪在并非主要用于脂肪储存的组织中积累，从而导致肥胖增加和糖尿病前期综合征的发展。
