Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.
Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.
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DOI：
10.1186/1758-5996-6-104
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发表时间：
2014
影响因子：
4.8
通讯作者：
Cincotta AH
中科院分区：
文献类型：
--
作者：
Ezrokhi M;Luo S;Trubitsyna Y;Cincotta AH
高血压、促炎和肥胖状态与外周和肝脏胰岛素抵抗密切相关（合成代谢综合征[MS]）。肝脏促炎通路已被证明可启动或加剧肝脏胰岛素抵抗，并导致脂肪肝，这与多发性硬化症有关。先前对季节性肥胖动物的研究表明，下丘脑多巴胺能张力的昼夜节律相依赖性增加在维持瘦弱、胰岛素敏感的状态中起重要作用。然而，驱动这种多巴胺能作用的机制尚未被充分描述，这种多巴胺能功能对MS上述参数的影响，特别是对肝脏炎症和脂质和葡萄糖代谢的关键肝内调节因子的影响从未被研究过。因此，本研究在非季节性MS模型-高血压肥胖SHR大鼠中研究了每日定时给药溴隐肽（一种强效多巴胺D2受体激动剂）对a)腹内侧下丘脑儿茶酚胺活性，b) MS和c)肝脏炎症和糖脂代谢关键调节因子的肝脏蛋白水平的影响。每天光周期维持14小时的16周龄SHR大鼠，在光抵消前1小时每天用溴隐肽（10 mg/kg, i.p）或载药治疗16天，在第14天记录血压，然后用于腹内侧下丘脑儿茶酚胺活性的体内微透析或牺牲用于分析MS因素和肝脏代谢调节因子。正常Wistar大鼠作为野生型对照，测量下丘脑活动、体脂水平和胰岛素敏感性。溴隐肽治疗显著降低腹内侧下丘脑去甲肾上腺素和血清素水平至正常范围，收缩压和舒张压，腹膜后体脂肪水平，血浆胰岛素和葡萄糖水平以及HOMA-IR相对于载药治疗的SHR对照组。与SHR对照组相比，这种治疗还降低了血浆c反应蛋白、瘦素和去甲肾上腺素水平，并显著提高了血浆脂联素水平。最后，与对照SHR大鼠相比，溴隐肽治疗显著降低了肝脏几种促炎途径蛋白的水平，以及脂肪生成、糖异生和游离脂肪酸氧化的主要转录激活因子的水平。这些发现表明，在SHR大鼠中，定时每日多巴胺激动剂治疗可改善与MS相关的下丘脑和神经内分泌病变，并且这些神经内分泌事件与肝脏代谢的转变相关联，从而增强了升高的脂肪生成和糖异生能力的降低。这种肝脏效应可能部分由高胰岛素血症和交感神经张力的同时降低以及肝内炎症的减少所驱动。本文的在线版本（doi:10.1186/1758-5996-6-104）包含补充材料，可供授权用户使用。
The hypertensive, pro-inflammatory, obese state is strongly coupled to peripheral and hepatic insulin resistance (in composite termed metabolic syndrome [MS]). Hepatic pro-inflammatory pathways have been demonstrated to initiate or exacerbate hepatic insulin resistance and contribute to fatty liver, a correlate of MS. Previous studies in seasonally obese animals have implicated an important role for circadian phase-dependent increases in hypothalamic dopaminergic tone in the maintenance of the lean, insulin sensitive condition. However, mechanisms driving this dopaminergic effect have not been fully delineated and the impact of such dopaminergic function upon the above mentioned parameters of MS, particularly upon key intra-hepatic regulators of liver inflammation and lipid and glucose metabolism have never been investigated. This study therefore investigated the effects of timed daily administration of bromocriptine, a potent dopamine D2 receptor agonist, on a) ventromedial hypothalamic catecholamine activity, b) MS and c) hepatic protein levels of key regulators of liver inflammation and glucose and lipid metabolism in a non-seasonal model of MS - the hypertensive, obese SHR rat. Sixteen week old SHR rats maintained on 14 hour daily photoperiods were treated daily for 16 days with bromocriptine (10 mg/kg, i.p.) or vehicle at 1 hour before light offset and, subsequent to blood pressure recordings on day 14, were then utilized for in vivo microdialysis of ventromedial hypothalamic catecholamine activity or sacrificed for the analyses of MS factors and regulators of hepatic metabolism. Normal Wistar rats served as wild-type controls for hypothalamic activity, body fat levels, and insulin sensitivity. Bromocriptine treatment significantly reduced ventromedial hypothalamic norepinephrine and serotonin levels to the normal range and systolic and diastolic blood pressures, retroperitoneal body fat level, plasma insulin and glucose levels and HOMA-IR relative to vehicle treated SHR controls. Such treatment also reduced plasma levels of C-reactive protein, leptin, and norepinephrine and increased that of plasma adiponectin significantly relative to SHR controls. Finally, bromocriptine treatment significantly reduced hepatic levels of several pro-inflammatory pathway proteins and of the master transcriptional activators of lipogenesis, gluconeogenesis, and free fatty acid oxidation versus control SHR rats. These findings indicate that in SHR rats, timed daily dopamine agonist treatment improves hypothalamic and neuroendocrine pathologies associated with MS and such neuroendocrine events are coupled to a transformation of liver metabolism potentiating a reduction of elevated lipogenic and gluconeogenic capacity. This liver effect may be driven in part by concurrent reductions in hyperinsulinemia and sympathetic tone as well as by reductions in intra-hepatic inflammation. The online version of this article (doi:10.1186/1758-5996-6-104) contains supplementary material, which is available to authorized users.