Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats
Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats
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DOI：
10.1016/s0306-4522(02)00447-5
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发表时间：
2002-01-01
期刊：
影响因子：
3.3
通讯作者：
Scarpace, PJ
中科院分区：
文献类型：
--
作者：
Li, G;Klein, RL;Scarpace, PJ
白细胞介素-6（IL-6）是一种多功能细胞因子，可能在能量调节中发挥作用。使用重组腺相关病毒载体表达鼠白细胞介素-6（rAAV-IL-6），我们研究了慢性的中央表达的IL-6对雄性Sprague-Dawley大鼠的摄食量，体重和肥胖的影响，并探讨了潜在的机制。将rAAV-IL-6直接递送到大鼠下丘脑中抑制了体重增加和内脏肥胖，而不影响5周内的食物摄入。rAAV-IL-6增强肩胛间棕色脂肪组织（BAT）中的解偶联蛋白1（UCP 1）蛋白水平。为了研究UCP 1的诱导和体重的减轻是否依赖于BAT的交感神经支配，我们将rAAV-IL-6或对照载体施用到肩胛间BAT单侧去神经的大鼠的下丘脑中。在21天内，rAAV-IL-6处理的大鼠和对照载体处理的大鼠之间的食物消耗或体重没有差异。rAAV-IL-6递送增加了神经支配的BAT垫中的UCP 1 mRNA和蛋白水平，但不增加去神经支配的BAT垫中的UCP 1 mRNA和蛋白水平。由磷酸化信号转导子和转录激活子3（P-STAT 3）水平指示的下丘脑IL-6信号转导在第21天升高6倍，但在第35天恢复到对照水平。然而，细胞因子信号转导抑制因子-3 mRNA水平在第21天和第35天均显著升高。这些数据表明，CNS中IL-6的慢性升高降低了体重增加和内脏肥胖，而不影响食物摄入。该机制涉及BAT中UCP 1的交感神经诱导，并且推测BAT中的产热增强。此外，慢性中枢IL-6刺激使以升高的P-STAT 3水平的逆转为特征的IL-6信号转导脱敏。由Elsevier Science Ltd代表IBRO发布。
Interleukin-6 (IL-6) is a multifunctional cytokine that may have a role in energy regulation. Using a recombinant adeno-associated viral vector expressing murine interleukin-6 (rAAV-IL-6), we examined the chronic effects of centrally expressed IL-6 on food intake, body weight and adiposity in male Sprague-Dawley rats, and investigated the underlying mechanisms. Direct delivery of rAAV-IL-6 into rat hypothalamus suppressed weight gain and visceral adiposity without affecting food intake over a 5-week period. rAAV-IL-6 enhanced uncoupling protein 1 (UCP1) protein levels in interscapular brown adipose tissue (BAT). To investigate if the induction of UCP1 and the reduction in body weight are dependent on sympathetic innervation of BAT, we administered rAAV-IL-6 or a control vector into the hypothalamus of rats in which the interscapular BAT was unilaterally denervated. Over 21 days, there was no difference in food consumption or body weight between rAAV-IL-6- and control vector-treated rats. rAAV-IL-6 delivery increased UCP1 mRNA and protein levels in innervated BAT pads but not denervated BAT pads. Hypothalamic IL-6 signal transduction indicated by phosphorylated signal transducer and activator of transcription 3 (P-STAT3) levels, was elevated by 6-fold at day 21, but returned to control levels by day 35. However, the suppressor of cytokine signaling-3 mRNA level was significantly elevated both at day 21 and day 35. These data demonstrate that chronic elevation of IL-6 in the CNS reduces body weight gain and visceral adiposity without affecting food intake. The mechanism involves sympathetic induction of UCP1 in BAT and, presumably, enhanced thermogenesis in BAT. Furthermore, chronic central IL-6 stimulation desensitizes IL-6 signal transduction characterized by reversal of elevated P-STAT3 levels. Published by Elsevier Science Ltd on behalf of IBRO.