Kim Y B, Uotani S, Pierroz D D, Flier J S, Kahn B B
Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215, USA.
Endocrinology. 2000 Jul;141(7):2328-39. doi: 10.1210/endo.141.7.7536.
To determine whether leptin signal transduction is exerted directly upon insulin-sensitive tissues in vivo, we examined the ability of iv leptin to acutely stimulate phosphorylation of STAT3, STAT1, and MAPK, and activities of PI 3-kinase and Akt, in insulin-sensitive tissues of normal rats. Both leptin (1 mg/kg iv x 3 min) and insulin (10 U/kg iv x 3 min) stimulated tyrosine phosphorylation of STAT3 5.6- to 6.0-fold and of STAT1 4.0-fold in adipose tissue. Leptin tended to increase STAT3 phosphorylation in liver and muscle. Both hormones also increased MAPK phosphorylation: leptin increased it 3.2- to 3.8-fold in adipose tissue and liver, whereas insulin stimulated MAPK phosphorylation 5.0-fold in adipose tissue, 6.8-fold in liver, and 2.5-fold in muscle. Leptin was much less effective than insulin at stimulating IRS pathways. Leptin increased IRS-1-associated PI 3-kinase activity in adipose tissue only 2.0-fold (P < 0.01) compared with the 10-fold effect of insulin. IRS-2-associated PI 3-kinase activity was increased 1.7-fold (P < 0.01) by leptin in liver and 6-fold by insulin. Akt phosphorylation and activity were not changed by leptin but increased with insulin. Lower concentrations of leptin (10 and 50 microg/kg) also stimulated STAT3 phosphorylation in fat. These effects appear to be direct because 3 min after leptin intracerebroventricular injection, phosphorylation of STAT3, STAT1, and MAPK were not stimulated in hypothalamus or adipose tissue. Furthermore, leptin activated STAT3 and MAPK in adipose tissue explants ex vivo and in 3T3-L1 adipocytes. Leptin did not activate STAT3 or MAPK in adipose tissue of db/db mice. Thus, leptin rapidly activates signaling pathways directly at the level of insulin sensitive tissues through the long-form leptin receptor, and these pathways overlap with, but are distinct from, those engaged by insulin.
为了确定瘦素信号转导是否在体内直接作用于胰岛素敏感组织，我们检测了静脉注射瘦素对正常大鼠胰岛素敏感组织中信号转导及转录激活蛋白3（STAT3）、信号转导及转录激活蛋白1（STAT1）和丝裂原活化蛋白激酶（MAPK）磷酸化以及磷脂酰肌醇-3激酶（PI 3-激酶）和蛋白激酶B（Akt）活性的急性刺激能力。瘦素（1 mg/kg静脉注射×3分钟）和胰岛素（10 U/kg静脉注射×3分钟）均可使脂肪组织中STAT3的酪氨酸磷酸化增加5.6至6.0倍，使STAT1的酪氨酸磷酸化增加4.0倍。瘦素倾向于增加肝脏和肌肉中STAT3的磷酸化。两种激素还均可增加MAPK的磷酸化：瘦素使脂肪组织和肝脏中的MAPK磷酸化增加3.2至3.8倍，而胰岛素使脂肪组织中的MAPK磷酸化增加5.0倍，肝脏中增加6.8倍，肌肉中增加2.5倍。在刺激胰岛素受体底物（IRS）途径方面，瘦素的效果远不如胰岛素。与胰岛素10倍的作用效果相比，瘦素仅使脂肪组织中与IRS-1相关的PI 3-激酶活性增加2.0倍（P<0.01）。瘦素使肝脏中与IRS-2相关的PI 3-激酶活性增加1.7倍（P<0.01），而胰岛素使其增加6倍。瘦素未改变Akt的磷酸化和活性，但胰岛素可使其增加。较低浓度的瘦素（10和50μg/kg）也可刺激脂肪组织中STAT3的磷酸化。这些作用似乎是直接的，因为在脑室内注射瘦素3分钟后，下丘脑或脂肪组织中STAT3、STAT1和MAPK的磷酸化未受到刺激。此外，瘦素可在体外激活脂肪组织外植体和3T3-L1脂肪细胞中的STAT3和MAPK。瘦素未激活db/db小鼠脂肪组织中的STAT3或MAPK。因此，瘦素通过长型瘦素受体在胰岛素敏感组织水平直接快速激活信号通路，这些通路与胰岛素所激活的通路重叠但又有所不同。
