Immune regulation of adipose tissue mass

脂肪组织量的免疫调节

基本信息

批准号：
9233105
负责人：
Anthony W Ferrante
金额：
$ 35.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-14 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233105
关键词：
Adipocytes Adipose tissue Animals Apoptosis Apoptotic Blood Circulation Body Weight Body Weight decreased Body fat Cells Cellular Stress Data Development Dyslipidemias Eating Energy Metabolism Fatty acid glycerol esters Goals High Fat Diet Human Genome Hypertrophy ITGAX gene Immune Immune system Individual Inflammatory Leptin Lipids Lipodystrophy Malignant - descriptor Mammals Measures Metabolism Modeling Molecular Mouse Strains Mus Natural Increases Natural Killer Cells Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Pathway interactions Play Population Predisposition Reaction Recruitment Activity Resistance Role Signal Pathway Signal Transduction Stress System Testing Therapeutic Thinness Tissue Expansion Tissues Up-Regulation Variant Viral Weight Weight Gain base biological adaptation to stress combat design genome wide association study immunoregulation macrophage non-alcoholic fatty liver novel therapeutics public health relevance receptor reduced food intake response

项目摘要

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.

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之前体重的反应：脂肪量的减少会激活增加食物摄入量和减少能量的系统支出，相反，过度喂养和快速脂肪组织扩张会减少食物摄入并增加能量消耗。近二十年前，瘦素的发现揭示了防止体内脂肪减少的中枢回路。从那时起，瘦素在防御身体脂肪方面所调节的细胞和分子途径得到了深入而富有成效的研究。然而，防止脂肪量快速膨胀的系统尚未得到充分研究和表征。事实上，关键组成部分在很大程度上仍然不为人所知。在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。该系统的核心组成部分是脂肪组织巨噬细胞（ATM）中促凋亡信号的激活。随着脂肪组织的扩张，ATM 的数量增加并积累大量脂质，增加细胞应激及其细胞凋亡的易感性。在研究对高脂肪饮食引起的肥胖的易感性各不相同的小鼠品系中，我们发现循环自然杀伤 (NK) 细胞群的大小可预测脂肪组织 NK 细胞的含量、CD11c+ ATM 群的大小以及对体重增加。循环系统和脂肪组织中 NK 细胞浓度最高的动物的 CD11c+ ATM 较少，并且能够抵抗肥胖的发展。传统上，NK 细胞识别并诱导恶性细胞、病毒感染细胞和某些应激细胞群的细胞凋亡。我们发现肥胖会增加脂肪组织中 NK 细胞识别的应激信号 (RAET1e) 的表达，并特别上调其在载脂 CD11c+ ATM 中的表达，而在具有高 NK 细胞的菌株中，这种表达会减少。这些数据表明 NK 细胞靶向 CD11c+ ATM 的凋亡可以限制脂肪量的扩张。事实上，在肥胖小鼠中直接激活 CD11c+ ATM 细胞凋亡，但在瘦小鼠中则不然，可以减少食物摄入并诱导体重减轻，且没有炎症反应或脂肪营养不良的证据。我们建议测试（1）基因减少或增加 NK 细胞靶向 ATM 凋亡是否会可预测地减少或增加高脂肪喂养小鼠的脂肪量（2）ATM 凋亡诱导的体重减轻是否会增加能量消耗并需要瘦素，以及（3 ）过度喂养的小鼠是否会激活 NK 细胞靶向 ATM 细胞凋亡，以限制脂肪组织扩张。实现本申请的目标将确定通过有针对性地操纵脂肪组织免疫细胞来减少或限制脂肪组织质量的潜在治疗策略。