Distributed neural control of energy expenditure

描述(申请人提供)：肥胖和超重的人的流行率急剧增加。肥胖引起的2型糖尿病和心血管疾病的并存使人们的注意力集中在开发有效治疗方法的必要性上。这些治疗的目标来自基础科学研究。中枢神经系统控制能量摄入和能量消耗，但对调节控制的特定回路和神经化学物质的了解仍然相当有限。拟议中的实验将产生数据，这些数据将有助于定义神经电路，这些神经电路控制由(1)黑素皮质素受体(MCR)激活和(2)口腔接触食物驱动的能量消耗。因此，这项建议与临床药物开发和公共卫生有关。MC4R基因突变是人类肥胖最常见的单基因原因。带有MC4R突变的动物吃得过多，消耗的能量更少。这项建议的目的是根据初步数据形成的，这些数据来自于口服喂养的神经学完好的大鼠、灌胃喂养的完好的和慢性去大脑的大鼠(来自前脑的神经连接被消除)。这些数据提出了两个假设--前脑处理介导了口服营养维持所见的交感神经张力增加，以及口腔维持对于在完整动物中通过脑干MCR兴奋触发能量反应是必要的-以及携带MCR的脑干尾侧核是交感调节支出反应的作用部位。这些实验：(1)确定口服营养递送(与匹配的胃营养递送相比)中交感张力的增加是否对于MCR触发的交感神经系统介导的能量消耗反应是必要的；(2)确定在尾侧脑干中特定的MCR承载核团对MCR触发的能量消耗的贡献；以及(3)定义处理口头感觉输入的前脑核团，增加交感张力，从而在尾侧脑干“门”MCR信号的能量效应。心率、核心和棕色脂肪组织温度以及活动度的测量将在口服和灌胃完整和去大脑的大鼠、使用针对脑干尾侧核(中缝苍白核、延髓头端腹外侧外侧核和孤束核)的实质内插管的大鼠以及在室旁核有细胞毒性损伤的大鼠中进行。

DESCRIPTION (provided by applicant): The prevalence of obese and overweight humans has increased dramatically. The type 2 diabetes and cardiovascular disease comorbidities of obesity focus attention squarely on the need to developm effective treatments. Targets for those treatments come from basic science research. The central nervous sytem controls energy intake and energy expenditure but knowledge of the specific circuits and neurochemicals mediating control remains quite limited. The proposed experiments will yield data that will contribute to defining the neural circuits that control energy expenditure driven by (1) melanocortin receptor (MCR) activation and (2) oral contact with food. As such, this proposal is relevant to clinical drug development and to public health. Mutations in the MC4R gene are the most common monogenetic cause of human obesity. Animals with MC4R mutations overeat and expend less energy. The aims of this proposal are shaped by preliminary data from oral-fed neurologically intact, and gavage-fed intact and chronic decerebrate rats (neural connections from forebrain are eliminated). Those data suggest two hypotheses - that forebrain processing mediates the increased sympathetic tone seen with oral nutrient maintenance and that oral maintenance is necessary for the triggering of energetic responses by brainstem MCR stimiulation in intact animals - and that caudal brainstem nuclei bearing MCRs are the site of action for sympathetically mediated expenditure responses. The experiments: (1) determine whether the increase in sympathetic tone seen with oral nutrient delivery (versus matched gastric nutrient delivery) is necessary for MCR-triggered, sympathetic nervous system mediated energy expenditure responses, (2) define the contribution of specific MCR bearing nuclei in the caudal brainstem to MCR triggered energy expenditure and (3) define the forebrain nuclei that process oral sensory input, increase sympathetic tone and thereby "gate" the energetic effect of MCR signaling in the caudal brainstem. Measurement of heart rate, core and brown adipose tissue temperature, and actiivty will be made in oral- and gavage-fed intact and decerebrate rats, in rats with intraparenchymal cannula aimed at caudal brainstem nuclei (raphe pallidus, rostral ventrolateral lateral medulla and nucleus tractus solitarius), and in rats with cytotoxic lesions of the paraventricular nucleus.