The Impact of Postnatal Overnutrition on the Adipose Tissue Immune System and Metabolic Inflammation

 描述(申请人提供)：在3岁以下的肥胖和超重儿童中发现白细胞激活的研究表明，肥胖引起的炎症的起源可能源于出生后早期。这与婴儿期快速生长与成人肥胖、代谢综合征、心血管疾病和2型糖尿病风险之间的强烈和独立的相关性相一致。推动这些关联的机制尚不清楚。由于先天和获得性免疫系统的激活对代谢性疾病的发展有重要的机械性贡献，我们认为出生后过度营养的长期不良代谢影响可能与免疫系统发育模式的改变有关。我们将提供初步数据，即出生后早期的特征是内脏脂肪组织中的免疫系统协调发展和脂肪生成。此外，出生后过度营养会放大内脏脂肪组织中髓系细胞的产生和炎症标记物。这些观察结果使我们假设，脂肪组织免疫系统对早期营养线索很敏感，这些营养线索可以改变一生中肥胖和代谢性炎症的风险。检验这一假说为理解出生后营养过剩可能如何影响发育中的免疫系统提供了一个机会，目前关于这一点的信息很少。我们知识中的这一差距是显著的，并限制了我们对早期营养与一生中肥胖和代谢性疾病风险之间的交集的理解。回答这些问题还将揭示脂肪组织白细胞在不同储存库中发育的机制。这项建议将检验核心假设，即出生后营养导致脂肪组织、巨噬细胞和T细胞的形成发生关键变化，从而对脂肪组织的发育产生负面影响，并增加成年后患代谢性疾病的风险。我们的方法将利用一种具有良好特征的小鼠出生后过度喂养(PNOF)模型，该模型基于对小鼠产仔大小的控制。该模型将被用来完成两个特定的目标：1)评估PNOF改变成年小鼠髓系细胞产生和增强脂肪组织炎症的机制。我们将检验这一假说，即造血干细胞的髓系潜能会因早期生长而改变。2)探讨PNOF对脂肪组织T细胞库特异性发育的影响。这是基于观察到小鼠在哺乳期专门发育的CD4+脂肪组织T细胞，因此在这一发育窗口期可能对过度营养高度敏感。在这项建议的最后，我们将阐明早期过度营养影响早期免疫系统发育并在一生中与代谢性疾病风险相结合的机制。

 DESCRIPTION (provided by applicant): Studies identifying leukocyte activation in obese and overweight children as young as 3 years of age suggest that the origins of obesity-induced inflammation may stem from the early postnatal period. This aligns with the strong and independent associations between rapid growth during infancy and the adult risk for obesity, metabolic syndrome, cardiovascular disease, and type 2 diabetes. The mechanisms that drive these associations are unclear. Since activation of the innate and adaptive immune system has a significant mechanistic contribution to the development of metabolic disease, we propose that the long-term adverse metabolic effects of postnatal over nutrition may relate to alterations in the developmental patterning of the immune system. We will present preliminary data that the early postnatal period is characterized by a coordinated development of the immune system in visceral adipose tissue and adipogenesis. Furthermore, postnatal over nutrition amplifies myeloid cell production and inflammatory markers in visceral adipose tissue. These observations lead us to hypothesize that the adipose tissue immune system is sensitive to early nutritional cues that can modify the risk for obesity and metabolic inflammation throughout life. Examining this hypothesis provides an opportunity to understand how postnatal nutrient excess may influence the developing immune system of which there is little information. This gap in our knowledge is significant and limits our understanding on the intersection between early nutrition and risk for obesity and metabolic disease throughout life. Answering these questions will also reveal the mechanisms by which adipose tissue leukocytes develop in different depots. This proposal will examine the central hypothesis that postnatal nutrition leads to critical alterationsin the formation of adipose tissue macrophages and T cells that negatively effects adipose tissue development and increases the risk for metabolic disease during adulthood. Our approach will utilize a well characterized model of postnatal overfeeding (PNOF) in mice based on manipulation of litter size. This model will be used to complete two specific aims: 1) To evaluate the mechanisms by which PNOF alters myeloid cell production and potentiates adipose tissue inflammation in adult mice. The hypothesis that myeloid potential of hematopoietic stem cells is altered by early growth will be examined. 2) To evaluate how PNOF alters the depot specific development of adipose tissue T cells. This is based on the observations that CD4+ adipose tissue T cells develop exclusively during lactation in mice and therefore may be highly sensitive to over nutrition during this developmental window. At the end of this proposal we will have elucidated the mechanisms by which early over nutrition influences the development of the early immune system and integrates with metabolic disease risk throughout life.