Roles of GM-CSF in Energy and Glucose Regulation

GM-CSF 在能量和血糖调节中的作用

• 批准号: 7145438
• 负责人: RANDY J SEELEY
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145438
• 关键词: adipose tissue; bioenergetics; biological signal transduction; carbohydrate balance; cell proliferation; cell type; central nervous system; colony stimulating factor; cytokine; gene expression; genetically modified animals; growth factor receptors; hypothalamus; immunocytochemistry; in situ hybridization; insulin sensitivity /resistance; laboratory mouse; laboratory rat; macrophage; nutrient intake activity; phosphorylation; protein localization; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): Obesity results when the number of calories ingested exceed the number of calories expended. The ability of the body to match caloric intake to caloric expenditure depends on a number of cytokines. Leptin is a cytokine released directly from adipocytes in proportion to the amount of body fat and acts on a variety of CNS circuits to regulate food intake, energy expenditure and peripheral glucose regulation. This proposal focuses upon another cytokine that parallels at least some of these actions of leptin: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). Our data indicate that when GM-CSF is administered into the CNS, it produces reductions in food intake and body weight that cannot be attributed to illness or motor impairment. Further, GM-CSF receptors can be found in several key hypothalamic nuclei linked to the control of food intake including the arcuate nucleus, which also shows high expression of the leptin receptor. Finally, mice that do not make GM-CSF show increased food intake and body fat. These data point to an important role for GM-CSF in the control of energy balance and the aims of this proposal focus upon elucidating key aspects of GM-CSF's biological function. First, our data implicate central production of GM- CSF as contributing to the regulation of energy balance. Consequently, we want to do map GM-CSF receptor distribution and identify the neurochemicals made by neurons that express GM-CSF receptors. We also will identity the locations and cellular types that produce GM-CSF in the CNS. Second, both leptin and GM-CSF are cytokines with similar actions on food intake and energy balance. In this aim we will test the hypothesis that GM-CSF's actions on food intake and energy balance are produced by activating aspects of the leptin receptor intracellular signaling cascade. Third, our preliminary data indicates that despite their increased adipose stores, GM-CSF mice show evidence of lowered adipose-tissue inflammation. Consequently, we hypothesize a separate function for GM-CSF in adipose tissue to contribute to the inflammatory cascade that links obesity to insulin resistance. To test this hypothesis we will measure macrophage accumulation and expression of various cytokines in adipose tissue in GM-CSF deficient mice. The aims presented here are an important step in unveiling the specific roles that GM-CSF plays in the normal regulation of body weight and its potential connection to the pathology of diabetes.

描述（由申请人提供）：当摄入的卡路里数超过消耗的卡路里数时会导致肥胖。身体使热量摄入与热量消耗相匹配的能力取决于许多细胞因子。瘦素是一种细胞因子，直接从脂肪细胞中释放，与身体脂肪的量成比例，并作用于各种中枢神经系统回路，以调节食物摄入，能量消耗和外周葡萄糖调节。这项建议集中在另一种细胞因子，平行至少有一些这些行动的瘦素：粒细胞巨噬细胞集落刺激因子（GM-CSF）。我们的数据表明，当GM-CSF进入中枢神经系统，它产生的食物摄入量和体重的减少，不能归因于疾病或运动障碍。此外，GM-CSF受体可以在与控制食物摄取相关的几个关键下丘脑核中发现，包括弓状核，其也显示瘦素受体的高表达。最后，不产生GM-CSF的小鼠表现出食物摄入量和体脂增加。这些数据指出了GM-CSF在控制能量平衡中的重要作用，并且该提议的目的集中于阐明GM-CSF的生物学功能的关键方面。首先，我们的数据暗示中枢产生的GM-CSF有助于调节能量平衡.因此，我们希望绘制GM-CSF受体分布图，并确定表达GM-CSF受体的神经元产生的神经化学物质。我们还将确定在CNS中产生GM-CSF的位置和细胞类型。其次，瘦素和GM-CSF都是细胞因子，对食物摄入和能量平衡具有相似的作用。在这个目标中，我们将测试的假设，即GM-CSF的行动对食物摄入量和能量平衡产生的激活方面的瘦素受体细胞内信号级联。第三，我们的初步数据表明，尽管它们的脂肪储存增加，GM-CSF小鼠显示出脂肪组织炎症降低的证据。因此，我们假设GM-CSF在脂肪组织中的单独功能有助于将肥胖与胰岛素抵抗联系起来的炎症级联反应。为了验证这一假设，我们将测量GM-CSF缺陷小鼠脂肪组织中巨噬细胞的积累和各种细胞因子的表达。本文提出的目的是揭示GM-CSF在体重正常调节中的特定作用及其与糖尿病病理学的潜在联系的重要一步。