Zvonic Sanjin, Cornelius Peter, Stewart William C, Mynatt Randall L, Stephens Jacqueline M
Department of Biological Sciences, Louisiana State University, Baton Rouge 70803, USA.
J Biol Chem. 2003 Jan 24;278(4):2228-35. doi: 10.1074/jbc.M205871200. Epub 2002 Nov 6.
Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFRalpha) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRalpha and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRalpha expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor gamma, acrp30, adipocyte-expressed STAT proteins, or C/EBPalpha. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFRalpha receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene expression, and the specific receptor for this cytokine is induced in rodent models of obesity/type II diabetes.
睫状神经营养因子（CNTF）主要因其作为破裂神经胶质细胞释放的损伤因子，防止神经元变性的作用而为人所知。然而，CNTF在多种肥胖/II型糖尿病啮齿动物模型中也显示出能导致体重减轻，而一种修饰形式在人类中也能导致体重减轻。给予CNTF可以纠正或改善与这些肥胖模型相关的高胰岛素血症、食欲亢进和高脂血症。为了研究CNTF对脂肪细胞的影响，我们检测了脂肪细胞分化过程中CNTF受体复合物蛋白（LIFR、gp130和CNTFRα）的表达以及CNTF对STAT、Akt和MAPK激活的影响。我们还检测了CNTF调节脂肪细胞转录因子和其他脂肪生成蛋白表达的能力。我们的研究清楚地表明，在脂肪细胞分化过程中，CNTF受体复合物的三个组分中的两个，即CNTFRα和LIFR的表达下降。相比之下，gp130的表达相对不受分化影响。此外，从前体脂肪细胞中STAT 3和Akt的激活情况判断，前体脂肪细胞比脂肪细胞对CNTF治疗更敏感。尽管在完全分化的3T3-L1脂肪细胞中CNTFRα表达水平降低，但用CNTF处理这些细胞会导致STAT 3的时间依赖性激活。长期处理脂肪细胞会导致脂肪酸合酶大幅减少以及SREBP-1水平显著下降，但对过氧化物酶体增殖物激活受体γ、acrp30、脂肪细胞表达的STAT蛋白或C/EBPα的表达没有影响。然而，CNTF导致IRS-1表达显著增加。与瘦的同窝仔相比，在四种肥胖/II型糖尿病啮齿动物模型的脂肪垫中，CNTFRα受体表达大幅诱导。此外，我们证明CNTF可以在体内激活脂肪组织和骨骼肌中的STAT 3。总之，CNTF影响脂肪细胞基因表达，并且在肥胖/II型糖尿病啮齿动物模型中诱导了这种细胞因子的特异性受体。
