Bjørbaek C, Elmquist J K, El-Haschimi K, Kelly J, Ahima R S, Hileman S, Flier J S
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Endocrinology. 1999 May;140(5):2035-43. doi: 10.1210/endo.140.5.6736.
Ciliary neurotrophic factor (CNTF) is a neurocytokine expressed in glial cells that acts on brain cells to promote gene expression, survival, and differentiation. When administered systemically, CNTF reduces food intake and body weight in rodents. Genes encoding suppressors of cytokine signaling (SOCS) are induced by cytokines that activate membrane receptors in the same class as those that are activated by CNTF. We therefore examined the ability of CNTF to induce expression of socs genes in brain and peripheral tissues of rats and mice. Peripheral CNTF administration to ob/ob mice rapidly induced SOCS-3 messenger RNA (mRNA) in hypothalamus, as determined by Northern blotting and quantitative RT-PCR, but had no effect on cytokine-inducible sequence (CIS), SOCS-1, or SOCS-2 mRNA. In situ hybridization histochemistry of hypothalamus from ob/ob mice and normal rats demonstrated that CNTF induced SOCS-3 mRNA in the arcuate nucleus (Arc). Strong hybridization signals were also detected in the ependymal lining of the ventricles and the subfornical organ. This hybridization pattern was distinct from that resulting from peripheral leptin treatment with overlapping hybridization patterns only in the Arc. CNTF also induced expression of CIS, SOCS-1, SOCS-2, and SOCS-3 mRNA in the liver, and SOCS-2 and SOCS-3 mRNA in the kidney. CNTF induced SOCS-3 mRNA and SOCS-3 protein levels in an astrocyte cell line. Transient expression of SOCS-3, but not CIS or SOCS-2, inhibited CNTF-induced signal transduction in astrocytes. In conclusion, SOCS-3 mRNA is specifically induced by CNTF in regions of the hypothalamus that are both overlapping and distinct from that induced by leptin. Similar to leptin, the Arc is likely to be a direct target of CNTF, and this region may play a role in the body weight-reducing effects of CNTF. SOCS-3 is a negative regulator of CNTF signal transduction, and inhibitors of SOCS-3 function may enhance endogenous CNTF signaling after neuronal injury or enhance the body weight-reducing effect of CNTF after peripheral administration.
睫状神经营养因子（CNTF）是一种在神经胶质细胞中表达的神经营养因子，作用于脑细胞以促进基因表达、存活和分化。当全身给药时，CNTF可减少啮齿动物的食物摄入量和体重。编码细胞因子信号转导抑制因子（SOCS）的基因由细胞因子诱导产生，这些细胞因子激活的膜受体与CNTF激活的膜受体属于同一类。因此，我们研究了CNTF诱导大鼠和小鼠脑及外周组织中socs基因表达的能力。通过Northern印迹法和定量RT-PCR测定，给ob/ob小鼠外周注射CNTF可迅速诱导下丘脑SOCS-3信使核糖核酸（mRNA），但对细胞因子诱导序列（CIS）、SOCS-1或SOCS-2 mRNA无影响。对ob/ob小鼠和正常大鼠下丘脑进行原位杂交组织化学分析表明，CNTF可诱导弓状核（Arc）中SOCS-3 mRNA的表达。在脑室室管膜内衬和穹窿下器官也检测到强杂交信号。这种杂交模式与外周注射瘦素后的杂交模式不同，仅在Arc区域有重叠的杂交模式。CNTF还可诱导肝脏中CIS、SOCS-1、SOCS-2和SOCS-3 mRNA以及肾脏中SOCS-2和SOCS-3 mRNA的表达。CNTF可诱导星形胶质细胞系中SOCS-3 mRNA和SOCS-3蛋白水平。SOCS-3的瞬时表达而非CIS或SOCS-2的瞬时表达可抑制星形胶质细胞中CNTF诱导的信号转导。总之，SOCS-3 mRNA在与瘦素诱导区域重叠且不同的下丘脑区域中由CNTF特异性诱导。与瘦素类似，Arc可能是CNTF的直接靶点，该区域可能在CNTF减轻体重的作用中发挥作用。SOCS-3是CNTF信号转导的负调节因子，SOCS-3功能抑制剂可能会增强神经元损伤后内源性CNTF信号转导，或增强外周给药后CNTF减轻体重的作用。
