A Genetic Model for Understanding the Metabolic Syndrome/Obesity Relationship

描述(由申请人提供)：肥胖率的增加增加了代谢综合征的发生率。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小鼠的遗传或饮食诱导肥胖是一种经常使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减轻。初步证据表明，尽管肾上腺素能敏感度正常，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NEFA利用率的降低，以及3)确定MC3-R-/-小鼠的NEFA释放减少是否减轻代谢综合征。第一个目标将包括严格测定MC3-R和MC4-R对白色脂肪组织交感神经张力(WAT)的影响，作为减少NEFA释放的机制。这组实验受到MC3/4-R共同刺激增加Wat交感神经音调的报道的鼓舞(Brito等人)。2007年；Nogueiras等人。2007)。目的1检测WT、MC4-R-/-和MC3-R-/-小鼠WAT对IP受体激动剂和拮抗剂的敏感性，明确WT、MC4-R-/-和MC3-R-/-小鼠WAT基础去甲肾上腺素(NE)和去甲肾上腺素(NE)代谢，以及中枢MC3-R对WAT基础NE和NE转化的药理阻断和刺激作用。游离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要求。因此，目标2将专注于野生型(WT)和MC3-R-/-小鼠的快速诱导蛋白质代谢。为了达到最终目标，我们将在MC3-R-/-小鼠中诱导NEFA动员后评估代谢综合征相关免疫标记物。此外，我们将防止DIO小鼠的脂肪酸动员，并检查代谢综合征的严重性。这些研究的结果将确定MC3-R在脂肪酸动员和骨骼肌周转中的作用，以及评估改变的脂肪酸动员对MC3-R-/-小鼠减弱的代谢综合征的作用。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的可行性。

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.