The Role of TNF Alpha in Obesity

描述(申请人提供)：这个项目是基于最近认识到肥胖，特别是内脏肥胖，是一种慢性炎症性疾病，其特征是大量巨噬细胞迁移到脂肪组织，导致局部和血浆细胞因子水平增加。这些变化的后果被认为与胰岛素抵抗和代谢综合征有因果关系。特别是，血浆中高水平的炎性细胞因子，特别是肿瘤坏死因子-1(TNF1)，已被认为是几种代谢和心血管疾病的重要危险因素，在动物模型中，TNF1的减少可以缓解肥胖的许多有害影响。有令人信服的证据表明，肥胖道路上重要的第一步是脂肪组织合成TNF1的增加，这反过来又刺激前脂肪细胞和局部内皮细胞将巨噬细胞招募到脂肪组织中。随着炎症信号分子的增加以及脂肪细胞和巨噬细胞的相互交叉刺激，这种情况继续螺旋式上升。TNF1和其他炎症信号分子最终达到足够高的水平，可以在血浆中检测到。由于来自脂肪组织的TNF1在体内循环，并到达不同的受体群体，因此，在特定部位和选择性受体上，TNF1活性在肥胖和胰岛素抵抗的病因中的作用尚不清楚。我们有初步证据表明，TNF1的一个重要作用部位在大脑，在那里它与其他影响能量摄入的信号相互作用。拟议的实验将(1)检验这样的假设，即TNF1在大脑中作用以控制能量平衡，具体地说，TNF1在大脑内的作用在提高中枢胰岛素敏感性的同时降低全身胰岛素敏感性。一项相关的假设是，TNF1在有全身性胰岛素抵抗的动物(例如高脂饮食(HFD)诱导的肥胖)的大脑中更有效；(2)评估游离(游离；可溶)TNF1和膜结合TNF1在TNF1对能量平衡影响中的相对贡献；以及(3)确定皮下脂肪组织、肠系膜脂肪组织或脂肪组织驻留巨噬细胞是否单独(或联合)足以引起代谢综合征症状的TNF1。实验将使用正常(野生型)小鼠和缺乏TNF1或其受体的小鼠，或者缺乏TACE的小鼠，TACE是一种裂解结合在膜上的TNF1以释放TNF1的酶。与公共卫生相关：内脏肥胖被认为是一种慢性炎症性疾病，其特征是脂肪组织中巨噬细胞数量增加，血浆中肿瘤坏死因子-1(TNF1)等细胞因子水平升高，被认为会导致胰岛素抵抗。拟议的实验将检验TNF1在大脑中作用于控制食物摄入量和全身胰岛素敏感性的假设，并确定哪种形式的TNF1是关键。实验将使用正常(野生型)小鼠和缺乏TNF1或其受体的小鼠。

DESCRIPTION (provided by applicant): This project is based upon the relatively recent realization that obesity, and especially visceral obesity, is a chronic inflammatory condition characterized by migration of high numbers of macrophages into the adipose tissue, with consequent increased local and plasma levels of cytokines. The consequences of these changes are thought to be causally linked to insulin resistance and the metabolic syndrome. In particular, high levels of inflammatory cytokines in the plasma, and especially tumor necrosis factor-1 (TNF1), have been recognized as an important risk factor for several metabolic and cardiovascular disorders, and in animal models reductions in TNF1 ameliorate many of the deleterious effects of obesity. There is compelling evidence that an important initial step along the road to obesity is an increase of TNF1 synthesis by adipose tissue, and that this in turn stimulates preadipocytes and local endothelial cells to recruit macrophages into the adipose tissue. This continues as a spiraling situation of increased inflammatory signaling molecules and mutual cross-stimulation of adipocytes and macrophages. TNF1 and other inflammatory signaling molecules eventually reach high enough levels to be detected in the plasma. Because TNF1 from adipose tissue circulates throughout the body and reaches diverse receptor populations, the role of TNF1 activity at specific sites, and at selective receptors, in the etiology of obesity and insulin resistance is not known. We have preliminary evidence that one important site of TNF1 action is in the brain, where it interacts with other signals that influence energy intake. Proposed experiments will (1) test the hypothesis that TNF1 acts in the brain to control energy homeostasis, and specifically that TNF1 action within the brain increases central insulin sensitivity while simultaneously decreasing systemic insulin sensitivity. A related hypothesis is that TNF1 is more effective in the brains of animals that have systemic insulin resistance, such as high-fat diet (HFD) induced obesity; (2) assess the relative contributions of free (unbound; soluble) TNF1 and membrane-bound TNF1 in the effects of TNF1 on energy balance; and (3) determine whether subcutaneous adipose tissue, mesenteric adipose tissue, or adipose tissue-resident macrophages are individually (or in combination) sufficient sources of TNF1 to elicit symptoms of the metabolic syndrome. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors or else mice lacking TACE, the enzyme that cleaves membrane-bound TNF1 to free TNF1. PUBLIC HEALTH RELEVANCE: Visceral obesity is recognized to be a chronic inflammatory condition characterized by high numbers of macrophages in adipose tissue and elevated plasma levels of cytokines such as tumor necrosis factor-1 (TNF1) that is thought to lead to insulin resistance. Proposed experiments will test the hypothesis that TNF1 acts in the brain to control food intake and systemic insulin sensitivity, and determine which form of TNF1 is critical. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors.