BLRD Merit Review Research Career Scientist (RCS) Award (IK6)

肥胖症及其相关并发症的流行，包括2型糖尿病和心血管疾病， 在过去的几十年里急剧增加。众所周知，一种免疫成分 导致代谢性疾病的病因学--尤其是在肥胖的情况下。例如，几乎所有的 已证实存在的免疫细胞存在于脂肪组织(AT)中。AT中的驻留巨噬细胞 被认为通过各种体内平衡功能促进AT的发育和正常功能。在.期间 体重增加，AT中所有免疫细胞的数量和表型都会发生变化，从而使整体环境发生变化 变得促炎，在组织和全身水平上促进胰岛素抵抗。哈希特实验室 目前在这一新兴的免疫代谢领域有两个主要的研究领域： 对减肥和体重循环的免疫记忆：虽然减肥是减少 肥胖对新陈代谢的负面影响，很明显，持续的减肥很难实现。一连串的 减重后体重增加会导致“体重循环”。有趣的是，几项针对人类的研究 证明体重循环会增加患代谢性疾病的风险。哈提斯博士和其他人 已发表的数据显示，在体重增加期间，AT的抗原反应。因此，她提出了这个假说 体重循环导致T细胞驱动的二次免疫反应，从而加剧AT的炎症， 导致局部和全身胰岛素抵抗(IR)。此外，她已经开始研究巨噬细胞 也可以“记住”肥胖环境中的一种过程，称为训练有素的先天免疫。这项工作是由 由她的退伍军人荣誉奖和由美国心脏协会颁发的新创新奖。 巨噬细胞铁处理：哈蒂斯博士的团队在AT发现了一组新的巨噬细胞，这些巨噬细胞 对控制局部铁浓度至关重要，从而有助于脂肪生成和保护 氧化应激。她的实验室最近的进展为确定常驻AT的角色提供了一个极好的机会 巨噬细胞在铁相关的AT稳态调控中的作用内源性免疫代谢，即燃料利用和 细胞的生物能量学和外源性免疫新陈代谢，即影响周围环境的分泌产物 组织环境，是影响巨噬细胞对组织的贡献的可操作属性 动态平衡。我们将确定铁循环如何影响AT免疫代谢作用的两个臂 巨噬细胞，从而影响全身胰岛素的作用。这项工作是由新的R01资助的。 哈斯特博士在这一领域发表了100多篇同行评议的手稿，发表在影响较大的期刊上，包括 糖尿病，自然医学，我J.Physiol.还有摩尔。梅塔布。她一直保持着一支强大的年轻队伍 她是她团队中的科学家，并热衷于培养下一代免疫代谢专家。哈斯蒂医生的 研究与退伍军人高度相关，因为退伍军人的肥胖率和代谢性疾病的比率甚至更高 而不是一般的平民人口。哈提斯博士和她的团队所做的工作对我们更好地 了解肥胖加速代谢性疾病的免疫调节机制。

The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease, has increased dramatically in the past several decades. It is well-established that an immune component contributes to the etiology of metabolic diseases – especially when driven by obesity. For example, nearly all of the immune cells in existence have been shown to reside in adipose tissue (AT). Resident macrophages in AT are thought to contribute to development and proper function of the AT by various homeostatic functions. During weight gain, the numbers and phenotypes of all of the immune cells in AT change such that the overall milieu becomes pro-inflammatory, promoting insulin resistance at the tissue and systemic levels. The Hasty laboratory currently has 2 main areas of investigation in this burgeoning area of immunometabolism: Immunologic memory to weight loss and weight cycling: While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. Bouts of weight loss followed by subsequent weight-gain lead to “weight-cycling”. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. Dr. Hasty and others have published data showing antigenic responses in AT during weight gain. Thus, she has developed the hypothesis that weight-cycling results in a T cell-driven secondary immune response that heightens inflammation in AT, leading to local and systemic insulin resistance (IR). In addition, she has begun to study whether macrophages also “remember” the obesogenic environment in a process called trained innate immunity. This work is funded by her VA Merit Award and by a new Innovation award from the American Heart Association. Macrophage iron handling: Dr. Hasty’s group discovered a novel population of macrophages in AT that are critical for control of local iron concentrations, thereby contributing to adipogenesis and to protection from oxidative stress. Her laboratory’s recent advances offer an excellent opportunity to define a role for resident AT macrophages in iron-related control of AT homeostasis. The intrinsic immunometabolism, i.e. fuel utilization and bioenergetics of the cell, and extrinsic immunometabolism, i.e. secreted products that affect the surrounding tissue environment, are manipulable properties that influence how macrophages contribute to tissue homeostasis. We will determine how iron cycling influences both arms of the immunometabolic role of AT macrophages, thereby influencing systemic insulin action. This work is funded by a new R01. Dr. Hasty has published over 100 peer-reviewed manuscripts in this area in high impact journals including Diabetes, Nature Medicine, Am. J. Physiol. and Mol. Metab. She has always maintained a strong cohort of young scientists within her group, and is keen on training the next generation of immunometabolism experts. Dr. Hasty’s research is highly relevant to Veterans as rates of obesity and metabolic disease are even higher in Veteran’s than in the general civilian population. The work performed by Dr. Hasty and her team are critical for us to better understand immune-mediated mechanisms of obesity-accelerated metabolic disease.