Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss
Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss
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DOI：
10.1152/ajpendo.00451.2006
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发表时间：
2007-07-01
影响因子：
5.1
通讯作者：
Scarpace, Philip J.
中科院分区：
文献类型：
--
作者：
Li, Gang;Zhang, Yi;Scarpace, Philip J.
为了研究脑干黑素皮质素系统在长期能量调节中的作用，我们评估了f344 * bn成年型肥胖大鼠尾侧脑干proopiomelanocortin （POMC）过量产生的影响。将编码POMC基因的重组腺相关病毒载体传递至后脑孤立束核（NTS），评估食物摄入量、体重、葡萄糖和脂肪代谢、棕色脂肪组织产热、神经肽和黑素皮质素受体mRNA水平。在42天内，POMC的递送导致食物摄入量和体重持续减少，并改善胰岛素敏感性。死亡时，重组腺相关病毒载体pomc处理的大鼠与对照大鼠相比，NTS中α -黑色素细胞刺激激素增加了近21倍，而下丘脑α -黑色素细胞刺激激素保持不变。内脏脂肪减少37%；肝脏和肌肉组织甘油三酯含量分别下降26%和47%；血清甘油三酯和非酯化脂肪酸分别减少35%和34%；比目鱼肌乙酰辅酶a羧化酶磷酸化水平升高63%；褐色脂肪组织解偶联蛋白1增加30%；黑素皮质素3受体的表达下降了60%，而神经肽Y、豚鼠相关蛋白和MC4受体mRNA水平在NTS中保持不变。总之，NTS中POMC的过表达产生了一种特征不减的吞咽症，这与下丘脑中POMC过表达后的厌食症、快速反应有独特的不同。持续的厌食反应可能是由于NTS中代偿元件的缺失，如刺痛症相关蛋白表达的增加，这表明黑素皮质素激活脑干可能是缓解肥胖的可行策略。
To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At death, in recombinant adeno-associated viral vector-POMC-treated rats vs. control rats, alpha-melanocyte-stimulating hormone in NTS increased nearly 21-fold, whereas hypothalamic alpha-melanocyte-stiinulating hormone remained unchanged. Visceral adiposity decreased by 37%; tissue triglyeride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyeride and nonesterified fatty acids were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; brown adipose tissue uncoupling protein 1 increased by 30%; and melanocortin 3 receptor expression declined by 60%, whereas neuropeptide Y, agouti-related protein, and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different from the anorexic, tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased agouti-related protein expression, suggesting melanocortin activation of the brain stem may be a viable strategy to alleviate obesity.