Neuroendocrine Regulation of Adipocyte Metabolism

脂肪细胞代谢的神经内分泌调节

• 批准号: 7590807
• 负责人: MATTHIAS H TSCHOP
• 金额: $ 38.73万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590807
• 关键词: Adipocytes; Adipose tissue; Adrenergic Receptor; Agonist; Area; Autonomic nervous system; Biochemistry; Body Weight; Brain; Brain Stem; CREB1 gene; CRH gene; Cardiovascular Diseases; Cell Nucleus; Cell physiology; Communication; Data; Dependovirus; Deposition; Diabetes Mellitus; Dose; Eating; Electrophysiology (science); Endocrine system; Energy Metabolism; Enzymes; Equilibrium; Euglycemic Clamping; Fatty acid glycerol esters; Gene Expression; Genes; Genetic; Glucose Clamp; Health; Hepatic; Hepatocyte; Hypothalamic structure; Indirect Calorimetry; Infusion procedures; Insulin; Knockout Mice; Knowledge; Laboratories; Lateral; Lipid Biochemistry; Lipid Mobilization; Lipids; Lipolysis; Liver; Malignant Neoplasms; Mediating; Mediation; Melanocortin 4 Receptor; Metabolic; Metabolism; Microinjections; Molecular; Molecular Models; Mus; Mutate; Neuraxis; Neurons; Neuropeptides; Neuropharmacology; Neurosecretory Systems; Norepinephrine; Nutrient; Obesity; Operative Surgical Procedures; Organ; Pancreas; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Prevention; Prevention strategy; Rattus; Regulation; Reporting; Rest; Role; SHU 9119; Series; Site; Structure of dorsomedial hypothalamic nucleus; Sympathetic Nervous System; System; Testing; Thermogenesis; Time; Triglyceride Metabolism; Triglycerides; Very low density lipoprotein; Virus; alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; base; energy balance; feeding; ghrelin; glucose and insulin clamps; in vivo; insight; knock-down; lipid biosynthesis; lipid metabolism; melanocortin receptor; molecular modeling; mouse model; muscle metabolism; nerve supply; obesity treatment; paraventricular nucleus; protein expression; public health relevance; receptor; research study; respiratory; response; small hairpin RNA; tool

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.

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-构成了我们这个时代的主要健康威胁之一。几个神经内分泌回路已被确定为肥胖的调节器。更好地了解这些途径和特定能量平衡组分之间的关系，目前被认为是确定有效治疗肥胖的最有前途的策略之一。虽然已经积累了大量的洞察力，关于控制食物摄入量，很少有人知道直接中枢神经系统的分子控制细胞脂质储存。我们最近观察到，在CNS黑皮质素受体系统的直接和间接失活或刺激后，白色脂肪组织和肝脏甘油三酯代谢发生了强效且不依赖于喂养的变化。为了进一步剖析这一现象，我们结合联合收割机神经药理学和基因缺失的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。具体而言，我们将结合联合收割机细胞核特异性显微注射在大鼠中枢神经系统与病毒介导的基因破坏和突变的小鼠模型，以澄清黑皮质素受体群体中的中枢神经系统区域调节外周甘油三酯代谢的关键组成部分，独立于食物摄入。根据这些结果，我们将测试这些CNS黑皮质素受体是否采用下游神经肽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，外科手术和遗传学工具的组合来特定地破坏传出ANS。这些研究将阐明中枢神经系统黑皮质素系统如何“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。 公共卫生关系：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通信，并基于这些知识，开发预防和治疗肥胖和糖尿病的新策略。