Roles of GM-CSF in Energy and Glucose Regulation

描述(由申请人提供)：当摄入的卡路里数量超过消耗的卡路里数量时，就会导致肥胖。身体将卡路里摄入量与卡路里消耗相匹配的能力取决于许多细胞因子。瘦素是一种直接从脂肪细胞释放的细胞因子，作用于多种中枢神经系统回路，调节食物摄入、能量消耗和外周葡萄糖调节。这项建议关注的是另一种细胞因子，它至少与瘦素的部分作用类似：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被注入中枢神经系统时，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，在下丘脑的几个与食物摄取控制有关的关键核团中也可以发现GM-CSF受体，包括弓状核，它也显示出瘦素受体的高表达。最后，没有产生GM-CSF的小鼠表现出更多的食物摄入量和体内脂肪。这些数据表明了GM-CSF在能量平衡控制中的重要作用，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的中心产生有助于调节能量平衡。因此，我们希望绘制GM-CSF受体的分布图，并识别表达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都是细胞因子，在食物摄入和能量平衡方面具有相似的作用。在这个目标中，我们将检验这样一个假设，即GM-CSF对食物摄取和能量平衡的作用是通过激活细胞内瘦素受体信号级联的各个方面而产生的。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减轻的证据。因此，我们假设脂肪组织中的GM-CSF具有单独的功能，促进了将肥胖与胰岛素抵抗联系在一起的炎症级联反应。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聚集和各种细胞因子的表达。这里提出的目标是揭示GM-CSF在正常体重调节中扮演的特定角色以及它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.