Immunologic memory to metabolic cycling

肥胖及其相关并存的患病率，包括2型糖尿病和 心血管疾病(CVD)在过去的几十年里急剧增加。而重量 减重是减少肥胖带来的负面代谢后果的理想方法，很明显 持续减肥是很难实现的。事实上，只有20%的人失去了至少10%的 体重能够保持2年以上的减重。这些减肥运动 随之而来的体重增加导致了“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。而当 人们认识到了举重循环的潜在有害影响，重量循环的机制是 骑自行车会增加代谢功能障碍，目前尚不清楚。在过去的十年里，我们已经达到了 了解免疫系统在肥胖的病理后果中起着关键作用。 新陈代谢器官，如肝脏、肌肉和脂肪组织(AT)积累免疫细胞， 从而影响实质细胞的胰岛素敏感性。特别是，肥胖会导致 炎性AT巨噬细胞和AT T淋巴细胞(ATT)数量显著增加。 有趣的是，在肥胖的AT中，T细胞的积累似乎是由抗原驱动的，也是 以存储单元的形成为特征的。确定举重自行车是否会改变免疫力 在AT中的反应，我们发展了一个小鼠的体重循环模型，使用交替的高脂肪(HF)和 低脂(LF)饮食喂养。与在人类身上看到的相似；体重循环的小鼠增加了 与体重增加的小鼠相比，空腹血糖水平和全身糖耐量受损 但没有骑车(体重增加控制)。此外，AT特异的胰岛素信号在 体重循环的小鼠。在研究结束时，AT中的巨噬细胞群没有变化 在数量和表型上。而ATT数量和多个TH1相关基因的表达 在体重循环小鼠的AT中基因显著增加。这些数据表明， 体重循环在AT中诱导强大的T细胞驱动的适应性免疫反应，并提示 体重循环实际上会诱导第二次适应性免疫反应。因此，总体假设 这一应用的目的是：体重循环导致加速的二次适应性免疫 加重AT炎症，导致局部和全身性胰岛素抵抗的反应。 这一假设将在以下3个目标中得到检验：1)确定重量循环是否会改变 ATT的表型和功能；2)确定体重循环是否诱导二次免疫反应 3)确定体重循环是否调节调节性T细胞(Treg)表型和 功能。

The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease (CVD), has increased dramatically in the past several decades. 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. In fact, only 20% of people who lose at least 10% of their body weight are able to maintain that loss for greater than 2 years. These 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. While the potentially deleterious effects of weight-cycling are recognized, the mechanisms by which weight- cycling increases metabolic dysfunction remain unknown. During the past decade, we have come to understand that the immune system plays a key role in the pathological consequences of obesity. Metabolic organs such as the liver, muscle, and adipose tissue (AT) accumulate immune cells that subsequently impact the insulin sensitivity of the parenchymal cells. In particular, obesity results in a dramatic increase in the number of inflammatory AT macrophages and AT T lymphocytes (ATTs). Interestingly, the accumulation of T cells in obese AT appears to be antigen-driven and is also characterized by the formation of memory cells. To determine if weight cycling alters immune responses in AT, we developed a mouse model of weight cycling using alternating high fat (HF) and low fat (LF) diet feeding. Similar to what is seen in humans; the weight-cycled mice had increased fasting glucose levels and impaired systemic glucose tolerance compared to mice that gained weight but did not cycle (weight-gain controls). Furthermore, AT-specific insulin signaling was abolished in the weight-cycled mice. At the end of the study, the macrophage populations in AT were unchanged in their number and phenotype. However, ATT number and the expression of multiple TH1-associated genes were significantly increased in the AT of the weight-cycled mice. These data demonstrate that weight cycling induces a potent T cell-driven adaptive immune response in the AT and suggest that weight cycling actually induce a secondary adaptive immune response. Thus, the overall hypothesis of this application is: weight-cycling results in an accelerated secondary adaptive immune response that heightens inflammation in AT, leading to local and systemic insulin resistance. This hypothesis will be tested in the following 3 aims: 1) To determine whether weight cycling alters ATT phenotype and function; 2) To determine if weight cycling induces secondary immune responses in AT; 3) To determine whether weight cycling modulates regulatory T cell (Treg) phenotype and function.