Wang J L, Chinookoswong N, Scully S, Qi M, Shi Z Q
Department of Pharmacology, Amgen, Inc., Thousand Oaks, California 91320, USA.
Endocrinology. 1999 May;140(5):2117-24. doi: 10.1210/endo.140.5.6681.
We have recently shown that leptin enhances systemic insulin sensitivity and whole body glucose utilization in the rat. This study examines our hypothesis that leptin has differential effects in regulating glucose utilization among the tissues, i.e. stimulating glucose utilization in brown adipose tissue (BAT) and skeletal muscle but suppressing glucose utilization in white adipose tissue (WAT) in normal male rats (275-350 g BW). The rats were treated with s.c. infusion of recombinant murine leptin (4 mg/kg x day) or vehicle (V) with Alzet osmotic pumps or with vehicle and pair-feeding (PF) for 7 days. Leptin significantly decreased food intake (leptin, 11.5 +/- 0.4 g/day; V, 16.8 +/- 1.5 g/day; P < 0.05) and body weight (maximum change, 5.0 +/- 0.2%; P < 0.05 vs. V) and lowered plasma triglyceride, insulin, and glucose levels, but raised beta-hydroxybutyrate levels. Glucose utilization by individual tissues was determined with an i.v. bolus of [1-(14)C]2-deoxyglucose (2-DG) after a 90-min hyperinsulinemic (2 mU/kg x min) euglycemic clamp. With leptin treatment, the 2-DG-determined glucose utilization in interscapular BAT was almost 3-fold that in V-treated rats and 70% greater than that in PF rats. In contrast, in the epididymal WAT, glucose utilization was reduced by leptin treatment to only 34% that in V-treated rats and 45% that in PF rats. Leptin increased 2-DG uptake by extensor digitorum longus muscle and soleus muscle compared with that in the V and PF groups. With leptin treatment, the GLUT4 glucose transporter mRNA and protein levels were increased in BAT, but decreased in WAT (both P < 0.05). There was no significant change in GLUT4 mRNA and protein expression in extensor digitorum longus muscle and soleus muscle. Oxygen consumption was significantly increased (32.1 +/- 7.4%) in BAT (139.0 +/- 8.2 nmole O2/30 min x 10(6) cells) of leptin-treated rats vs. that in V control rats (105.3 +/- 6.7 nmole O2/30 min x 10(6) cells). In conclusion, leptin has differential, tissue-specific effects on glucose and oxygen utilization, which contribute to the reduction in whole body adiposity by enhancing energy consumption in BAT and muscle while attenuating energy storage in WAT.
我们最近发现，瘦素可增强大鼠的全身胰岛素敏感性及整体葡萄糖利用率。本研究检验了我们的假设，即瘦素在调节各组织间葡萄糖利用方面具有不同作用，即在正常雄性大鼠（体重275 - 350克）中，刺激棕色脂肪组织（BAT）和骨骼肌的葡萄糖利用，但抑制白色脂肪组织（WAT）的葡萄糖利用。给大鼠皮下植入Alzet渗透泵，用重组鼠瘦素（4毫克/千克×天）或赋形剂（V）进行输注，或用赋形剂并配对喂食（PF），持续7天。瘦素显著降低了食物摄入量（瘦素组，11.5±0.4克/天；V组，16.8±1.5克/天；P < 0.05）和体重（最大变化，5.0±0.2%；与V组相比，P < 0.05），并降低了血浆甘油三酯、胰岛素和葡萄糖水平，但提高了β - 羟基丁酸水平。在90分钟高胰岛素血症（2毫单位/千克×分钟）正常血糖钳夹后，通过静脉推注[1 - （14）C]2 - 脱氧葡萄糖（2 - DG）来测定各组织的葡萄糖利用率。经瘦素治疗后，肩胛间BAT中由2 - DG测定的葡萄糖利用率几乎是V组治疗大鼠的3倍，比PF组大鼠高70%。相反，在附睾WAT中，瘦素治疗使葡萄糖利用率仅降至V组治疗大鼠的34%和PF组大鼠的45%。与V组和PF组相比，瘦素增加了趾长伸肌和比目鱼肌对2 - DG的摄取。经瘦素治疗后，BAT中GLUT4葡萄糖转运蛋白的mRNA和蛋白水平升高，但在WAT中降低（均P < 0.05）。趾长伸肌和比目鱼肌中GLUT4 mRNA和蛋白表达无显著变化。与V组对照大鼠（105.3±6.7纳摩尔O2/30分钟×10（6）个细胞）相比，瘦素治疗大鼠的BAT中氧消耗量显著增加（32.1±7.4%）（139.0±8.2纳摩尔O2/30分钟×10（6）个细胞）。总之，瘦素对葡萄糖和氧的利用具有不同的组织特异性作用，通过增强BAT和肌肉中的能量消耗，同时减少WAT中的能量储存，有助于降低全身肥胖程度。
