Immune regulation of adipose tissue mass

描述（由申请人提供）：哺乳动物调节脂肪量，因此在体重稳定的个体中，脂肪组织的增加或减少会激活有利于恢复到以前体重的反应：脂肪量的减少会激活一个增加食物摄入和减少能量消耗的系统，相反，过度喂养和脂肪组织的快速扩张会减少食物摄入和增加能量消耗。随着近20年前瘦素的发现，抵御体脂减少的中枢回路被揭示出来。从那时起，瘦素调节防御体脂肪的细胞和分子途径得到了深入而富有成果的研究。然而，防御脂肪量快速膨胀的系统还没有得到很好的研究和表征。事实上，关键的组成部分在很大程度上仍然模糊不清。在研究免疫细胞在新陈代谢中所起作用的过程中，我们发现了一个系统，我们认为它限制了脂肪团的扩张。该系统的核心组成部分是脂肪组织巨噬细胞（ATMs）中促凋亡信号的激活。随着脂肪组织的扩张，atm数量增加并积累大量脂质，增加细胞应激及其对凋亡的易感性。在研究对高脂肪饮食引起的肥胖易感性不同的小鼠品系时，我们发现循环自然杀伤（NK）细胞群的大小预测脂肪组织NK细胞含量、CD11c+ ATM细胞群的大小和对体重增加的抵抗力。在其循环和脂肪组织中NK细胞浓度最高的动物具有较少的CD11c+ atm，并且对肥胖的发展具有抵抗力。通常，NK细胞识别并诱导恶性、病毒感染和某些应激细胞群的凋亡。我们发现肥胖增加了脂肪组织中NK细胞识别的应激信号（RAET1e）的表达，并特异性上调其在富含NK细胞的CD11c+ atm中的表达。这些数据表明NK细胞靶向CD11c+ ATMs的凋亡可以限制脂肪团的扩大。事实上，直接激活肥胖小鼠（而非瘦小鼠）的CD11c+ atm细胞凋亡，可以减少食物摄入并诱导体重减轻，而没有炎症反应或脂肪营养不良的证据。我们打算测试(1)在高脂肪喂养的小鼠中，基因上NK细胞靶向凋亡的减少或增加是否可以预测脂肪量的减少或增加；(2)ATM细胞凋亡引起的体重减轻是否会增加能量消耗并需要瘦素；(3)过量喂养的小鼠是否会激活NK细胞靶向ATM细胞凋亡以限制脂肪组织的扩张。实现这一应用的目标将确定潜在的治疗策略，以减少或限制脂肪组织质量b靶向脂肪组织免疫细胞的操作。

DESCRIPTION (provided by applicant): Mammals regulate fat mass, so that in weight-stable individuals increases or reductions in adipose tissue activate responses that favor return to one's previous weight: A reduction in fat mass activates a system that increases food intake and reduces energy expenditure, and conversely, overfeeding and rapid adipose tissue expansion reduces food intake and increases energy expenditure. With the identification of leptin nearly two decades ago the central circuit that defends against reductions in body fat was revealed. Since then, the cellular and molecular pathways that leptin regulates in defense of body fat have been intensively and fruitfully studied. However, the systems that defend against rapid expansion of fat mass have been less well studied and characterized. Indeed, the key components remain largely obscure. During an effort to characterize the role that immune cells play in metabolism we uncovered a system that we believe limits fat mass expansion. The central component of this system is the activation of pro- apoptotic signaling in adipose tissue macrophages (ATMs). As adipose tissue expands, ATMs increase in number and accumulate large amounts of lipid, increasing cellular stress and their susceptibility to apoptosis. In studyig strains of mice that vary in their susceptibility to high fat diet-induced obesity, we found that te size of the circulating natural killer (NK) cell population predicts adipose tissue NK cell content the size of the CD11c+ ATM population, and resistance to weight gain. Animals with the highest concentration of NK cells in their circulation and adipose tissue have fewer CD11c+ ATMs and are resistant to the development of obesity. Classically, NK cells recognize and induce apoptosis in malignant, virally infected and certain populations of stressed cells. We found that obesity increases the expression of an NK cell-recognized stress signal (RAET1e) in adipose tissue and specifically upregulates its expression in lipid-laden CD11c+ ATMs that are reduced in strains with high NK cells. These data suggested that NK cell targeted apoptosis of CD11c+ ATMs could limit fat mass expansion. Indeed, direct activation of apoptosis of CD11c+ ATMs in obese, but not in lean mice, reduces food intake and induces weight loss, without evidence of an inflammatory reaction or lipodystrophy. We propose to test (1) whether genetically decreasing or increasing NK cell targeted apoptosis of ATMs will predictable reduce or increase fat mass in high fat fed mice (2) whether weight loss induced by ATM apoptosis increases energy expenditure and requires leptin, and (3) whether overfeeding mice activates NK cell targeted apoptosis of ATMs to limit adipose tissue expansion. Achieving the goals of this application will identify potential therapeutic strategies to reduce or limit adipose tissue mass b targeted manipulation of adipose tissue immune cells.