Roles of GM-CSF in Energy and Glucose Regulation

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，就会导致肥胖。身体将热量摄入与消耗相匹配的能力取决于许多细胞因子。瘦素是一种由脂肪细胞与体脂量成比例直接释放的细胞因子，作用于多种中枢神经回路，调节食物摄入、能量消耗和外周葡萄糖调节。这一建议着重于另一种细胞因子，至少与瘦素的某些作用相似：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进入中枢神经系统时，它会产生食物摄入量和体重的减少，这不能归因于疾病或运动障碍。此外，GM-CSF受体可以在控制食物摄入的几个关键下丘脑核中发现，包括弓状核，它也显示出瘦素受体的高表达。最后，不产生GM-CSF的小鼠表现出食物摄入量增加和体脂增加。这些数据表明GM-CSF在控制能量平衡中起着重要作用，本提案的目的集中在阐明GM-CSF生物学功能的关键方面。首先，我们的数据表明GM- CSF的集中产生有助于调节能量平衡。因此，我们想绘制GM-CSF受体分布图，并鉴定由表达GM-CSF受体的神经元产生的神经化学物质。我们还将确定中枢神经系统中产生GM-CSF的位置和细胞类型。其次，瘦素和GM-CSF都是对食物摄入和能量平衡具有相似作用的细胞因子。在这个目的中，我们将检验GM-CSF对食物摄入和能量平衡的作用是通过激活瘦素受体细胞内信号级联产生的假设。第三，我们的初步数据表明，尽管GM-CSF小鼠的脂肪储存增加，但它们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。本文提出的目标是揭示GM-CSF在正常体重调节中发挥的具体作用及其与糖尿病病理的潜在联系的重要一步。

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.