Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats
Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats
复制标题
DOI：
10.1096/fj.01-0164com
复制
发表时间：
2002-04-01
期刊：
影响因子：
4.8
通讯作者：
Sakata, T
中科院分区：
文献类型：
--
作者：
Hidaka, S;Yoshimatsu, H;Sakata, T
我们研究了长期集中注射瘦素对链脲佐菌素诱导的糖尿病（STZ-D）大鼠（胰岛素依赖性糖尿病模型）葡萄糖代谢的影响。当3杯。老鼠(-1) 。第(-1)天连续6天将瘦素注入第三脑室(STZ-LEP)，STZ-D大鼠血糖完全正常。当皮下注射相同剂量时没有看到效果。集中施用瘦素不影响外周胰岛素水平。 STZ-LEP 大鼠的进食量被抑制至非 STZ-D 对照大鼠的水平。当 STZ-D 大鼠与 STZ-LEP 大鼠的喂养量配对喂养时，高血糖没有改善。因此，STZ-LEP大鼠的血糖正常不可能是由于饲喂量减少所致。在 STZ-D 大鼠中，葡萄糖激酶 mRNA（糖酵解标志物）下调，而葡萄糖-6-磷酸酶 mRNA（糖异生标志物）和葡萄糖转运蛋白 (GLUT) 2（与肝脏释放葡萄糖有关）上调。 GLUT4、解偶联蛋白 (UCP) 1 和 UCP3 在棕色脂肪组织中下调。中央输注瘦素后，这些参数恢复正常。 STZ-D大鼠骨骼肌中GLUT4没有下调；然而，当大鼠接受瘦素治疗时，脂肪酸结合蛋白和肉碱棕榈酰转移酶I（脂肪酸利用和β-氧化的标记物）上调并恢复。脂肪酸利用率的增加和随后的减少表明 STZ-D 大鼠骨骼肌中葡萄糖摄取的减少，在中枢瘦素给药后恢复。我们的结论是，集中输注瘦素不是通过调节进食量或升高外周胰岛素来控制血糖，而是通过调节肝葡萄糖产生、外周葡萄糖摄取和能量消耗。本研究表明未来有可能开发出一类新型抗糖尿病药物，其作用集中且独立于胰岛素作用。
We examined the effects of chronic centrally administered leptin on the glucose metabolism of streptozotocin-induced diabetic (STZ-D) rats, a model for insulin-dependent diabetes mellitus. When 3 mug . rat(-1) . day(-1) of leptin was infused into the third ventricle for 6 consecutive days (STZ-LEP), STZ-D rats became completely euglycemic. The effect was not seen when the same dosage was administered s.c. Centrally administered leptin did not affect peripheral insulin levels. The feeding volume of STZ-LEP rats was suppressed to the level of non-STZ-D control rats. No improvement of hyperglycemia was noted when STZ-D rats were pair-fed to match the feeding volume of STZ-LEP rats. Thus, the euglycemia of STZ-LEP rats cannot be due to the decreased feeding volume. In the STZ-D rat, glucokinase mRNA, a marker of glycolysis, is down-regulated whereas glucose-6-phosphatase mRNA, a marker of gluconeogenesis, and glucose transporter (GLUT) 2, which is implicated in the release of glucose from liver, are up-regulated. GLUT4, uncoupling protein (UCP) 1, and UCP3 were down-regulated in brown adipose tissue. These parameters returned to normal upon central infusion of leptin. GLUT4 was not down-regulated in the skeletal muscle of STZ-D rats; however, fatty acid binding protein and carnitine palmitoyltransferase I, markers for utilization and beta-oxidation of fatty acids, were up-regulated and restored when the rats were treated with leptin. The increase and subsequent decrease of fatty acid utilization suggests a decrease of glucose uptake in the skeletal muscle of STZ-D rats, which was restored upon central leptin administration. We conclude that centrally infused leptin does not control serum glucose by regulating feeding volume or elevating peripheral insulin, but by regulating hepatic glucose production, peripheral glucose uptake, and energy expenditure. The present study indicates the possibility of future development of a new class of anti-diabetic agents that act centrally and independent of insulin action.