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

 描述（由申请人提供）：在3岁以下的肥胖和超重儿童中发现白细胞活化的研究表明，肥胖诱导的炎症可能起源于出生后早期。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关联一致。驱动这些关联的机制尚不清楚。由于先天性和适应性免疫系统的激活对代谢性疾病的发展具有重要的机制性贡献，我们认为出生后营养过度的长期不良代谢效应可能与免疫系统发育模式的改变有关。我们将提出初步的数据，出生后早期的特点是协调发展的免疫系统在内脏脂肪组织和脂肪形成。此外，出生后的营养过剩会增加骨髓细胞的产生和内脏脂肪组织中的炎症标志物。这些观察使我们假设脂肪组织免疫系统对早期营养线索敏感，可以改变一生中肥胖和代谢性炎症的风险。检查这一假设提供了一个机会，以了解如何产后营养过剩可能会影响发展中的免疫系统，其中有很少的信息。我们知识上的这一差距是巨大的，限制了我们对早期营养与肥胖和代谢疾病风险之间交叉的理解。阐明这些问题也将揭示脂肪组织白细胞在不同部位发育的机制。这项建议将检查中心假设，即产后营养导致脂肪组织巨噬细胞和T细胞形成的关键改变，对脂肪组织发育产生负面影响，并增加成年期代谢疾病的风险。我们的方法将利用一个充分表征的模型，出生后过度喂养（PNOF）的基础上操纵窝仔的小鼠。该模型将用于完成两个特定目的：1）评估PNOF改变成年小鼠骨髓细胞产生和增强脂肪组织炎症的机制。造血干细胞的髓样潜能被早期生长改变的假说将被检验。2)评估PNOF如何改变脂肪组织T细胞的储库特异性发育。这是基于以下观察结果，即CD4+脂肪组织T细胞仅在小鼠哺乳期间发育，因此在此发育窗口期间可能对过度营养高度敏感。在本提案的最后，我们将阐明早期营养过剩影响早期免疫系统发育的机制，并与终生代谢疾病风险相结合。

 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.