Distributed neural control of energy expenditure

描述（由申请人提供）：肥胖和超重人群的患病率急剧增加。肥胖引起的2型糖尿病和心血管疾病合并症将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，但对特定回路和调节控制的神经化学物质的了解仍然相当有限。拟议的实验将产生的数据将有助于定义由(1)黑素皮质素受体（MCR）激活和(2)口腔与食物接触驱动的控制能量消耗的神经回路。因此，这一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。MC4R突变的动物会暴饮暴食，消耗更少的能量。这一建议的目的是根据神经完整的口服喂养和灌食的完整和慢性失智大鼠的初步数据形成的（前脑的神经连接被消除）。这些数据提出了两种假设，即前脑处理介导了口服营养维持所见的交感神经张力的增加，口服维持对于在完整动物中通过脑干MCR刺激触发能量反应是必要的，以及携带MCR的尾侧脑干核是交感介导的消耗反应的作用部位。实验:(1)确定口服营养输送（相对于匹配的胃营养输送）中交感神经张力的增加是否对MCR触发的交感神经系统介导的能量消耗反应是必要的；(2)确定尾侧脑干中特定的MCR承受核对MCR触发的能量消耗的贡献；(3)确定处理口腔感觉输入的前脑核。增加交感神经张力，从而“限制”尾侧脑干MCR信号的能量效应。测量心率、核心和棕色脂肪组织温度和活动，测量的对象是口服和灌食的完整大鼠和去脑大鼠，采用脑实质内插管的大鼠，其目标是脑干尾侧核（苍白缝、延髓吻侧腹外侧外侧和孤束核），以及室旁核有细胞毒性病变的大鼠。

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.