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。代谢综合征相关疾病包括非胰岛素依赖型糖尿病(NIDDM)、非酒精性脂肪肝、高血压和心脏病。 C57BL/6J 小鼠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 (MC3-R) -/- C57BL/6J 小鼠的代谢综合征症状却显着减轻。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) 确定肾上腺素能张力在 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，以补偿能量受限的 MC3-R -/- 小鼠中 NEFA 可用性的下降，以及3) 确定 MC3-R -/- 小鼠中 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，作为减少 NEFA 释放背后的机制。 MC3/4-R 共刺激增加 WAT 交感神经张力的报告鼓励了这组实验（Brito 等人，2007 年；Nogueiras 等人，2007 年）。目标 1 将检查对 ip 注射的 β-激动剂和拮抗剂的敏感性，确定 WT、MC4-R -/- 和 MC3-R -/- 小鼠 WAT 中的基础去甲肾上腺素 (NE) 和 NE 转换，并确定药理学阻断的作用以及中枢 MC3-R 对 WAT 基础 NE 和 NE 周转的刺激。动员脂肪酸可以满足动物在饮食不足时的能量需求。在代谢应激期间无法动员脂肪酸，需要使用替代代谢燃料，MC3-R -/- 小鼠的数据表明，增加蛋白质代谢可能会满足代谢需求。因此，目标 2 将重点关注野生型 (WT) 和 MC3-R -/- 小鼠中快速诱导的蛋白质代谢。为了实现最终目标，我们将在 MC3-R -/- 小鼠中诱导 NEFA 动员后评估代谢综合征相关的免疫标记物。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 对脂肪酸动员和骨骼肌周转的作用，并评估改变的脂肪酸动员对 MC3-R -/- 小鼠的减毒代谢综合征的作用。这些发现将有助于评估药理学 MC3-R 操作作为减少肥胖相关并发症的治疗方法的可行性。