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

• 批准号: 7544771
• 负责人: Benjamin Jennings Renquist
• 金额: $ 4.68万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-02 至 2011-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544771
• 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; Diabetes Mellitus; 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; Insulin; 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; mouse Mc3r protein; non-alcoholic fatty liver; pressure; prevent; protein metabolism; receptor; research study; response; sterol esterase; therapeutic target

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。代谢综合征相关病症包括非胰岛素依赖型糖尿病（NIDDM）、非酒精性脂肪肝病、高血压和心脏病。C57 BL/6 J小鼠中遗传或饮食诱导的肥胖是代谢综合征的常用模型。然而，尽管肥胖增加，黑皮质素3受体（MC 3-R）-/-C57 BL/6 J小鼠表现出代谢综合征症状的显著减弱。初步证据表明，尽管肾上腺素敏感性正常，但非酯化脂肪酸（NEFA）动员的缺陷可能有助于保护肥胖的MC 3-R -/-小鼠免受代谢综合征的影响。我建议1）确定肾上腺素能紧张在MC 3-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，以补偿能量受限的MC 3-R -/-小鼠中NEFA可用性的降低，以及3）确定MC 3-R -/-小鼠中NEFA释放的降低是否会减轻代谢综合征。第一个目标将包括严格确定MC 3-R和MC 4-R对白色脂肪组织（WAT）交感神经张力的影响，作为NEFA释放减少背后的机制。这组实验受到MC 3/4-R共刺激增加WAT交感神经张力的报道的鼓舞（Brito等人，2007; Nogueiras等人，2007）。目的1将检查对ip注射的β-激动剂和拮抗剂的敏感性，鉴定WT、MC 4-R -/-和MC 3-R -/-小鼠的WAT中的基础去甲肾上腺素（NE）和NE周转，并鉴定中枢MC 3-R的药理学阻断和刺激对WAT基础NE和NE周转的作用。动员的脂肪酸用于满足动物在饮食不足时的能量需求。在代谢应激期间不能动员脂肪酸，需要使用替代代谢燃料，MC 3-R -/-小鼠中的数据表明，蛋白质代谢增加可能满足代谢要求。因此，目标2将关注野生型（WT）和MC 3-R -/-小鼠中的快速诱导蛋白质代谢。为了解决最终目标，我们将在MC 3-R -/-小鼠中诱导NEFA动员后评估代谢综合征相关的免疫标志物。此外，我们将防止DIO小鼠中的脂肪酸动员，并检查代谢综合征的严重程度。这些研究的结果将确定MC 3-R对脂肪酸动员和骨骼肌周转的作用，以及评估改变的脂肪酸动员对MC 3-R -/-小鼠代谢综合征减弱的作用。这些发现将有助于评估药理学MC 3-R操作作为减少肥胖相关并发症的治疗的可行性。