Neuroendocrine Regulation of Adipocyte Metabolism

描述(申请人提供)：肥胖及其并发症--如糖尿病、心血管疾病或癌症--构成了我们这个时代的主要健康威胁之一。一些神经内分泌回路已被确定为肥胖的调节因素。更好地了解这些途径和特定能量平衡成分之间的关系，目前被认为是寻找有效治疗肥胖症的最有前途的策略之一。虽然已经积累了大量关于控制食物摄入的见解，但对中枢神经系统直接控制细胞脂肪储存的分子知之甚少。我们最近观察到，在直接和间接失活或刺激中枢黑素皮质素受体系统后，白色脂肪组织和肝脏甘油三酯代谢发生了强有力的、不依赖于喂养的变化。为了进一步剖析这种现象，我们将神经药理学和基因缺失研究与自动间接量热法、胰岛素-葡萄糖钳、配对喂养模型和脂类代谢的分子生物化学相结合。具体地说，我们将结合大鼠中枢神经系统核特异性微量注射与病毒介导的基因干扰和突变的小鼠模型来阐明在哪些中枢神经系统区域调节外周甘油三酯代谢的关键成分独立于食物摄入量的黑素皮质素受体群体。在这些结果的指导下，我们将测试这些中枢神经系统黑素皮质素受体是否利用下游神经肽CRH/TRH和传出自主神经系统轴来控制肝脏和脂肪组织中的细胞脂代谢。对于这些研究，我们将使用电生理学和分子脂生物化学以及药理学、外科和遗传学工具的组合来定点干扰传出ANS。这些研究将阐明中枢神经系统黑素皮质素系统如何“远程”控制脂肪合成、脂肪沉积和脂肪动员之间的外周代谢平衡。与公共健康相关：肥胖及其并发症--如糖尿病、心血管疾病或癌症--构成了我们这个时代最重要的健康威胁之一，同时需要找到治疗肥胖的有效药物。我们实验室最近的实验结果表明，已知的调节体重的主要大脑网络之一，即所谓的黑素皮质素系统，直接与脂肪细胞和肝脏通信，以调节这些重要器官中沉积的脂肪量。我们将进行一系列实验，以阐明哪些神经和激素系统用于这种交流，并在此基础上开发预防和治疗肥胖症和糖尿病的新策略。

DESCRIPTION (provided by applicant): Obesity with its complications - such as diabetes, cardiovascular diseases or cancer - poses one of the predominant health threats of our times. Several neuroendocrine circuits have been identified as regulators of adiposity. A better understanding of the relationship between these pathways and specific energy balance components is currently regarded as one of the most promising strategies toward identifying an efficient treatment for obesity. While substantial insight has been accumulated regarding the control of food intake, little is known about a direct CNS molecular control of cellular lipid storage. We recently observed potent and feeding-independent changes in white adipose tissue and liver triglyceride metabolism following direct and indirect inactivation or stimulation of the CNS melanocortin receptor system. To further dissect that phenomenon we combine neuropharmacology and genetic deletion studies with automated indirect calorimetry, insulin-glucose clamps, pair feeding models, and molecular biochemistry of lipid metabolism. Specifically we will combine nucleus specific microinjections in the rat central nervous system with virus mediated gene disruption and mutated mouse models to clarify which melanocortin receptor population in which CNS region modulates key components of peripheral triglyceride metabolism independent from food intake. Guided by these results we will test if those CNS melanocortin receptors employ downstream neuropeptides CRH/TRH and the efferent autonomic nervous system axis to control cellular lipid metabolism in liver and adipose tissue. For these studies we will use electrophysiology and molecular lipid biochemistry as well as a combination of pharmacological, surgical and genetic tools to site-specifically disrupt the efferent ANS. These studies will elucidate how the CNS melanocortin system "remote" controls the peripheral metabolic balance between lipid synthesis, lipid deposition and lipid mobilization. PUBLIC HEALTH RELEVANCE: Obesity with its complications - such as diabetes, cardiovascular diseases or cancer - poses one of the most important health threats of our times, while efficient drugs for the cure from obesity need to be discovered. Recent results from experiments in our laboratory indicate that one of the major brain networks known to regulate body weight, the so called "melanocortin system", directly communicates with fat cells and the liver in order to regulate the amount of fat deposited in these important organs. We will perform a series of experiments to clarify which neuronal and hormonal systems are used for this kind of communication and, based on that knowledge, develop new strategies for the prevention and treatment of obesity and diabetes.