Neuroendocrine Regulation of Adipocyte Metabolism

描述（由申请人提供）：肥胖及其并发症，如糖尿病、心血管疾病或癌症，是我们这个时代主要的健康威胁之一。几种神经内分泌回路已被确定为肥胖的调节因子。更好地了解这些途径和特定能量平衡成分之间的关系，目前被认为是确定有效治疗肥胖的最有希望的策略之一。虽然在控制食物摄入方面已经积累了大量的见解，但对中枢神经系统直接控制细胞脂质储存的分子知之甚少。我们最近观察到白色脂肪组织和肝脏甘油三酯代谢在中枢神经系统黑素皮质素受体系统的直接和间接失活或刺激后发生了强有力的和不依赖于摄食的变化。为了进一步剖析这一现象，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、配对喂养模型和脂质代谢的分子生物化学相结合。具体来说，我们将结合大鼠中枢神经系统的核特异性显微注射与病毒介导的基因破坏和突变小鼠模型，以阐明中枢神经系统区域的黑素皮质素受体群体调节不依赖于食物摄入的外周甘油三酯代谢的关键成分。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质代谢。在这些研究中，我们将使用电生理学和分子脂质生物化学以及药理学、外科和遗传工具的结合来定点破坏输出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”控制脂质合成、脂质沉积和脂质动员之间的外周代谢平衡。公共卫生相关性：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，而治疗肥胖的有效药物需要被发现。我们实验室最近的实验结果表明，已知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沟通，以调节沉积在这些重要器官中的脂肪量。我们将进行一系列实验，以阐明哪些神经元和激素系统用于这种交流，并在此基础上制定预防和治疗肥胖和糖尿病的新策略。

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.