The Role of TNF Alpha in Obesity

描述（由申请人提供）：该项目基于相对较新的认识，即肥胖，尤其是内脏肥胖，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中，从而导致细胞因子的局部和血浆水平增加。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，尤其是肿瘤坏死因子-1 (TNF1)，已被认为是多种代谢和心血管疾病的重要危险因素，并且在动物模型中，TNF1 的减少可改善肥胖的许多有害影响。有令人信服的证据表明，通往肥胖之路的重要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。这种情况持续不断，炎症信号分子增加，脂肪细胞和巨噬细胞相互交叉刺激。 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 在全身循环并到达不同的受体群体，因此特定位点和选择性受体上的 TNF1 活性在肥胖和胰岛素抵抗的病因学中的作用尚不清楚。我们有初步证据表明 TNF1 作用的一个重要部位位于大脑中，它与影响能量摄入的其他信号相互作用。拟议的实验将 (1) 检验 TNF1 在大脑中发挥作用以控制能量稳态的假设，特别是 TNF1 在大脑中的作用增加中枢胰岛素敏感性，同时降低全身胰岛素敏感性。一个相关的假设是，TNF1 对具有全身性胰岛素抵抗的动物的大脑更有效，例如高脂饮食 (HFD) 引起的肥胖； (2) 评估游离（未结合；可溶）TNF1 和膜结合 TNF1 在 TNF1 对能量平衡的影响中的相对贡献； (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(或组合)是足以引发代谢综合征症状的TNF1来源。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（将膜结合 TNF1 裂解为游离 TNF1 的酶）的小鼠。公共健康相关性：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较多，血浆细胞因子水平升高，例如被认为会导致胰岛素抵抗的肿瘤坏死因子-1 (TNF1)。拟议的实验将检验 TNF1 在大脑中发挥作用以控制食物摄入和全身胰岛素敏感性的假设，并确定哪种形式的 TNF1 至关重要。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.