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A Genetic Model for Understanding the Metabolic Syndrome/Obesity Relationship

用于理解代谢综合征/肥胖关系的遗传模型

基本信息

批准号：
7920106
负责人：
Benjamin Jennings Renquist
金额：
$ 4.99万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-02 至 2011-08-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920106
关键词：
Address Adipocytes Adipose tissue Adrenergic Agents Agonist Amino Acids Animals Attenuated Biological Models Brain region Chronic Comparative Study Data Defect Depressed mood Development Diet Disease Employee Strikes Enzymes Esterified Fatty Acids Excretory function Exhibits Fasting Fatty Acids Fatty Liver Genes Genetic Genetic Models Genotype Glucose Intolerance Heart Diseases Heart Rate Hyperlipidemia Hyperphagia Hypertension Hypertrophy Immunologic Markers Incidence Inflammation Leptin Lesion Lipid Mobilization Lipolysis Liver diseases Measures Melanocortin 3 Receptor Melanocortin 4 Receptor Metabolic Metabolic stress Metabolic syndrome Metabolism Modeling Mus Muscle Muscle Proteins Nitrogen Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Obesity Phosphorylation Plasma Play Prevalence Proteins Reporting Role Severities Skeletal Muscle Symptoms Testing Therapeutic Time Wild Type Mouse adrenergic attenuation fatty acid metabolism hypolipidemia in vivo leptin receptor meetings mouse Mc3r protein non-alcoholic fatty liver pressure prevent protein metabolism receptor research study response sterol esterase therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The increased prevalence of obesity has increased the incidence of metabolic syndrome. Metabolic syndrome associated disorders include non-insulin dependent diabetes mellitus (NIDDM), non-alcoholic fatty liver disease, hypertension, and heart disease. Genetic or diet-induced obesity in the C57BL/6J mouse is a frequently employed model of metabolic syndrome. Yet, despite an increase in adiposity, the melanocortin 3 receptor (MC3-R) -/- C57BL/6J mouse exhibits a dramatic attenuation of the symptoms of metabolic syndrome. Preliminary evidence suggests that a defect in non-esterified fatty acid (NEFA) mobilization, despite normal adrenergic sensitivity, may serve to protect the obese MC3-R -/- mouse from metabolic syndrome. I propose to 1) determine the role of adrenergic tone in adipocyte hypertrophy and metabolism in the MC3-R -/- mouse, 2) identify alternative metabolic fuels compensating for decreased NEFA availability in the energy restricted MC3-R -/- mouse, and 3) determine if decreased NEFA release in the MC3-R -/- mouse attenuates metabolic syndrome. The first aim will include a rigorous determination of MC3-R and MC4-R effects on sympathetic tone in white adipose tissue (WAT), as a mechanism behind the reduced NEFA release. This set of experiments is encouraged by reports that MC3/4-R co-stimulation increases WAT sympathetic tone (Brito et al. 2007; Nogueiras et al. 2007). Aim 1 will examine sensitivity to ip injected ^-agonists and antagonists, identify basal norepinephrine (NE) and NE turnover in WAT of WT, MC4-R -/-, and MC3-R -/- mice, and identify the role pharmacological blockade and stimulation of central MC3-R on WAT basal NE and NE turnover. Mobilized fatty acids serve to meet the energy requirements of the animal during times of dietary insufficiency. An inability to mobilize fatty acids during metabolic stress, requires use of alternative metabolic fuels, data in the MC3-R -/- mouse suggests that increased protein metabolism may meet metabolic requirements. Therefore, aim 2 will focus on fast-induced protein metabolism in wild-type (WT) and MC3-R -/- mice. To address the final aim, we will assess metabolic syndrome associated immune markers after inducing NEFA mobilization in the MC3-R -/- mouse. Furthermore, we will prevent fatty acid mobilization in the DIO mouse and examine the severity of metabolic syndrome. Results from these studies will identify the role of MC3-R on fatty acid mobilization and skeletal muscle turnover, as well as evaluate the role of altered fatty acid mobilization on the attenuated metabolic syndrome of the MC3-R -/- mouse. These findings will help evaluate the viability of pharmacological MC3-R manipulation as a treatment to decrease obesity associated complications.

描述（由申请人提供）：肥胖患病率的增加增加了代谢综合征的发病率。代谢综合征相关疾病包括非胰岛素依赖型糖尿病（NIDDM）、非酒精性脂肪性肝病、高血压和心脏病。C57BL/6J小鼠的遗传性或饮食性肥胖是一种常用的代谢综合征模型。然而，尽管肥胖增加，黑素皮质素3受体(MC3-R) -/- C57BL/6J小鼠表现出代谢综合征症状的显著衰减。初步证据表明，尽管正常的肾上腺素能敏感性，但非酯化脂肪酸（NEFA）动员缺陷可能有助于保护肥胖MC3-R -/-小鼠免受代谢综合征的影响。我建议1)确定肾上腺素能调节在MC3-R -/-小鼠脂肪细胞肥大和代谢中的作用，2)确定替代代谢燃料，补偿能量受限的MC3-R -/-小鼠NEFA可用性的减少，3)确定MC3-R -/-小鼠NEFA释放的减少是否会减轻代谢综合征。第一个目标将包括严格确定MC3-R和MC4-R对白色脂肪组织（WAT）交感神经张力的影响，作为NEFA释放减少的机制。MC3/4-R共刺激增加WAT交感神经张力的报道鼓舞了这组实验（Brito et al. 2007; Nogueiras et al. 2007）。目的1将检测对ip注射^-激动剂和拮抗剂的敏感性，鉴定WT、MC4-R -/-和MC3-R -/-小鼠WAT中基础去甲肾上腺素（NE）和NE转换，并确定药物阻断和刺激中枢MC3-R对WAT基础NE和NE转换的作用。动员脂肪酸用于满足动物在饮食不足时的能量需求。在代谢应激期间无法调动脂肪酸，需要使用替代代谢燃料，MC3-R -/-小鼠的数据表明，增加的蛋白质代谢可能满足代谢需求。因此，aim 2将重点关注野生型（WT）和MC3-R -/-小鼠快速诱导的蛋白质代谢。为了解决最终的目的，我们将在诱导MC3-R -/-小鼠的NEFA动员后评估代谢综合征相关的免疫标志物。此外，我们将阻止DIO小鼠的脂肪酸动员，并检查代谢综合征的严重程度。这些研究的结果将确定MC3-R在脂肪酸动员和骨骼肌转换中的作用，并评估脂肪酸动员改变对MC3-R -/-小鼠代谢综合征的作用。这些发现将有助于评估MC3-R药理学操作作为减少肥胖相关并发症的治疗方法的可行性。