剔除腦內STAT3轉錄因子可修飾安非他命媒介的厭食作用

下視丘神經胜肽Y（NPY）可以促進食慾，類鴨片-黑色素细胞皮质素原(pro-opiomelanocortin)（POMC）可以抑制食慾。而安非他命可抑制食慾，因為它抑制NPY神經元和促進POMC神經元。而NPY及POMC相互作用的機轉不明，所以本研究在探討STAT3訊息傳遞是否參與其中。每天對大鼠注射安非他命，一天一次，連續4天，觀察下視丘NPY，POMC，黑色素受體3(MC3R)，PI3K和STAT3含量的表現，並使用腦室注射STAT3反意序列(antisense)抑制STAT3的表現，觀察STAT3的作用。實驗結果顯示攝食作用與NPY表現降低，且在第2天表現最大量降低，相反的，POMC，MC3R，PI3K和STAT3的表現增加，且在第2天表現最大量增加，類似的情況也發生在STAT3和DNA結合活性。側腦室注射STAT3反意序列，60分鐘後再注射安非他命，可以部分阻斷安非他命引起的厭食，並修飾NPY，POMC，MC3R和PI3K含量的表現，此結果說明STAT3有參與其中過程。因此PI3K-STAT3訊號傳遞參與了下視丘NPY和POMC對食慾控制的調節。此結果有助於安非他命食慾抑制機轉的理解和減肥藥的研發。

Background and purpose：Appetite suppression induced by amphetamine has been attributed to its inhibition of neuropeptide Y (NPY) neurons and activation of pro-opiomelanocortin(POMC) neurons in the hypothalamus.This study examined whether STAT3 signalling was involved in the action of amphetamine. Experimental approach：Rats were given amphetamine i.p. daily for 4 days. Changes in the expression of NPY, POMC, melanocortin receptor 3(MC3R), PI3K and STAT3 in the hypothalamus were assessed by RT-PCR and Western blotting. Intra cerebroventricular injection of antisense oligonucleotides to STAT3 were also used.Key results：Expression of foodintake and NPY decreased with a maximum effect on day 2 during amphetamine treatment.However,expression of POMC, MC3R, PI3K and STAT3 increased with a maximum response on day 2. Moreover, phosphorylation of STAT3 and its DNA binding activity increased and was expressed in a similar pattern. Infusion (i.c.v.) of STAT3 antisense at 60 min before dailt amphetamine treatment,could partly block amphetamine-induced anorexia and modulated expression of NPY, POMC, MC3R and PI3K, indicating the involvement of STAT3 signalling in amphetamine-treated rats.Conclusions and implications：Hypothalamic PI3K–STAT3 signalling participated in the regulation of NPY- and POMC-mediated appetite suppression. These findings may contribute to a better understanding of anorectic effect of amphetamine.