Immune regulation of adipose tissue mass

说明（由申请人提供）：哺乳动物调节脂肪量，使得在体重稳定的个体中脂肪组织的增加或减少激活有利于恢复到先前体重的反应：脂肪量的减少激活增加食物摄入并减少能量消耗的系统，相反，过度喂养和快速脂肪组织扩张减少食物摄入并增加能量消耗。近二十年前，随着瘦素的发现，防御体脂减少的中央回路被揭示出来。从那时起，瘦素在防御体脂肪中调节的细胞和分子途径已经被深入和富有成效地研究。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。 在努力描述免疫细胞在新陈代谢中的作用的过程中，我们发现了一个我们认为限制脂肪量扩张的系统。该系统的中心组成部分是激活脂肪组织巨噬细胞（ATM）中的促凋亡信号。随着脂肪组织的扩张，ATM的数量增加并积累大量的脂质，增加细胞应激及其对凋亡的易感性。在研究不同品系的小鼠对高脂饮食诱导的肥胖的易感性时，我们发现循环中自然杀伤（NK）细胞群体的大小预测了脂肪组织NK细胞含量、CD 11 c + ATM群体的大小以及对体重增加的抵抗力。在循环和脂肪组织中NK细胞浓度最高的动物具有较少的CD 11 c + ATM，并且抵抗肥胖的发展。传统上，NK细胞识别并诱导恶性、病毒感染和某些应激细胞群体的细胞凋亡。我们发现，肥胖增加了NK细胞识别的应激信号（RAET 1 e）在脂肪组织中的表达，并特异性上调了其在富含脂质的CD 11 c + ATM中的表达，而这些ATM在具有高NK细胞的菌株中减少。这些数据表明，NK细胞靶向的CD 11 c + ATM细胞凋亡可以限制脂肪量扩张。事实上，肥胖小鼠中CD 11 c + ATM细胞凋亡的直接激活，而非瘦小鼠，减少了食物摄入并诱导体重减轻，而没有炎症反应或脂肪代谢障碍的证据。我们提出测试（1）在高脂肪喂养的小鼠中，基因降低或增加NK细胞靶向的ATM凋亡是否将可预测地降低或增加脂肪量;（2）由ATM凋亡诱导的体重减轻是否增加能量消耗并需要瘦素;以及（3）过度喂养的小鼠是否激活NK细胞靶向的ATM凋亡以限制脂肪组织扩张。实现本申请的目标将鉴定通过脂肪组织免疫细胞的靶向操作来减少或限制脂肪组织质量的潜在治疗策略B。

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.