Interactions of sympathetic nervous and melanocortin systems in obesity reversal

交感神经和黑皮质素系统在肥胖逆转中的相互作用

• 批准号: 8069833
• 负责人: Cheryl Hope Vaughan
• 金额: $ 5.68万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069833
• 关键词: ART protein; Accounting; Adipocytes; Adipose tissue; Adult; Agonist; American; Animal Model; Animals; Area; Behavioral; Biochemical; Biochemistry; Biological; Biological Assay; Biology; Blood; Body fat; Brain; Brain Stem; Cardiovascular Diseases; Cellular biology; Clinical; Complement; Diabetes Mellitus; Dopamine; Event; Fatty acid glycerol esters; Food deprivation (experimental); Gene Expression; Glycerol; Hamsters; Harvest; Human; Hypertension; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Knowledge; Laboratories; Lighting; Lipase; Lipid Mobilization; Lipids; Lipolysis; Measures; Melanocortin 4 Receptor; Messenger RNA; Microinjections; Midbrain structure; Modeling; Molecular; Molecular Biology; Mutation; Nature; Neurons; Neurosciences; Nonesterified Fatty Acids; Norepinephrine; Obesity; Overweight; Peptides; Persons; Phodopus sungorus; Phosphorylation; Physiological; Physiology; Process; Proteins; Reporting; Risk; Rodent; Role; Siberian Hamster; Site; Stimulus; Sympathetic Nervous System; System; Techniques; Testing; Time; Training; Triglycerides; Ventricular; Visceral; Western Blotting; deprivation; genetic manipulation; in vitro testing; in vivo; in vivo Model; innovation; interest; lipid metabolism; melanocortin receptor; melanotan-II; nerve supply; neurochemistry; novel; perilipin; perilipin A; receptor; research study; response; sterol esterase

DESCRIPTION (provided by applicant): An estimated 65% of American adults are overweight or obese and this number is rising. There is emerging evidence that high amounts of visceral fat increases a person's risk for developing cardiovascular disease, hypertension and diabetes. More is known about the transition from lean to obese than the reverse. We use the Siberian hamster (Phodopus sungorus) animal model because they are obese during long 'summer-like' days in nature and naturally reverse to a leaner state in short 'winter-like' days. Therefore, these animals can be studied in the obese, lean and transition states by altering their lighting conditions in the laboratory thereby providing a biologically meaningful model without genetic manipulation. Reports from the Bartness laboratory have been instrumental in delineating connections between body fat and the brain and ascribing function to these connections. Neuronal influence on the sympathetic nervous system has been found to be the principle initiator of fat mobilization (lipolysis) in a fat depot specific manner; this is true in hamsters and humans. Changes in the processes involved in lipid mobilization can be assayed by measuring sympathetic drive and by-products of intracellular cascades (phosphorylation of perilipin, adipose triglyceride lipase) after sympathetic activation. The first specific aim proposes looking at changes in lipolysis using a new in vivo marker of phosphorylation -- perilipin, an intracellular protein that in the non-phosphorylated state protects lipid droplets from breakdown, as well as measuring sympathetic drive via norepinephrine turnover and finally glycerol and free fatty acid (products of lipolysis) concentrations in blood of food deprived hamsters. To our knowledge, this will be the first in vivo measure of phosphorylation of perilipin though it is well established as one of the last necessary steps of lipolysis in vitro. The second specific aim will test how specific brain sites involving the melanocortin system and the sympathetic nervous system circuits to fat is involved in lipolysis using the same measures as the first aim. This is important to understand because mutations of melanocortin peptides or receptors account for 6-8% cases of obesity seen in humans. Collectively, these experiments will test how regional changes in fat depots occur in response to environmental stimuli and neurochemical stimulation that activate brain-sympathetic nervous system-white fat connections to trigger lipolysis and thus are important to understand for obesity reversal. This will be accomplished using a unique, naturally occurring, intact, obese animal model employing innovative markers of lipolysis. Thus, the results of these studies will contribute important and relevant knowledge of the mechanisms of lipid mobilization and of the process of obesity reversal.

描述(申请人提供)：据估计，65%的美国成年人超重或肥胖，而且这一数字还在上升。有新的证据表明，内脏脂肪含量高会增加一个人患心血管疾病、高血压和糖尿病的风险。人们对从瘦到胖的转变比从瘦到胖的转变了解得更多。我们使用西伯利亚仓鼠的动物模型，因为它们在自然界中长时间的像夏天一样的日子里肥胖，在短暂的像冬天的日子里自然地变得更瘦。因此，通过改变实验室中的光照条件，这些动物可以在肥胖、瘦身和过渡状态下进行研究，从而提供了一个具有生物学意义的模型，而不需要遗传操作。来自Barness实验室的报告有助于描绘身体脂肪和大脑之间的联系，并将这些联系归因于功能。神经元对交感神经系统的影响已经被发现是脂肪动员(脂肪分解)的主要启动者，以一种特定的脂肪库方式；这在仓鼠和人类中是真实的。通过测量交感神经激活后的交感神经驱动和细胞内级联反应的副产物(Perilipin的磷酸化、脂肪甘油三酯脂肪酶)，可以分析参与脂肪动员的过程的变化。第一个具体目标是使用一种新的体内磷酸化标记物--Perilipin来观察脂肪分解的变化，Perilipin是一种细胞内蛋白质，在非磷酸化状态下保护脂肪液滴不被分解，并通过去甲肾上腺素的周转来测量交感神经驱动，最后测量缺乏食物的仓鼠血液中甘油和游离脂肪酸(脂肪分解产物)的浓度。据我们所知，这将是第一次在体内测量Perilipin的磷酸化，尽管这是体外脂解的最后必要步骤之一。第二个具体目标将使用与第一个目标相同的方法来测试涉及黑素皮质素系统和交感神经系统对脂肪的回路的特定大脑部位如何参与脂肪分解。了解这一点很重要，因为黑素皮质素多肽或受体的突变导致了人类肥胖病例的6-8%。总而言之，这些实验将测试脂肪库的局部变化如何响应环境刺激和神经化学刺激，这些刺激激活大脑-交感神经系统-白色脂肪连接以触发脂肪分解，因此了解这一点对于肥胖症的逆转非常重要。这将通过一种独特的、自然发生的、完整的、肥胖的动物模型来实现，该模型采用了创新的脂肪分解标记。因此，这些研究的结果将有助于对脂肪动员的机制和肥胖逆转过程的重要和相关的知识。