Immunologic memory to metabolic cycling

代谢循环的免疫记忆

基本信息

  • 批准号:
    10045934
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 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:
    2014-07-01 至 2022-09-30
  • 项目状态:
    已结题

项目摘要

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.
肥胖和相关合并症的患病率,包括2型糖尿病和 心血管疾病(CVD)在过去几十年中急剧增加。虽然体重 减肥是减少肥胖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 体重能够保持这种损失超过2年。这几次减肥 随后的体重增加导致“体重循环”。有趣的是,几项针对人类的研究 研究表明,体重循环会增加患代谢性疾病的风险。而 体重循环的潜在有害影响是公认的,体重循环的机制, 骑自行车增加代谢功能障碍仍然是未知的。在过去的十年里,我们来到了 了解免疫系统在肥胖的病理后果中起着关键作用。 肝脏、肌肉和脂肪组织(AT)等代谢器官积累免疫细胞, 随后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)的数量急剧增加。 有趣的是,肥胖AT中T细胞的积累似乎是抗原驱动的,并且也是免疫调节的。 其特征在于形成存储单元。为了确定体重循环是否会改变免疫功能, 在AT的反应,我们开发了一个小鼠模型的重量循环使用交替高脂肪(HF)和 低脂肪(LF)饮食喂养。与在人类中看到的相似;体重循环小鼠增加了 与体重增加的小鼠相比,空腹血糖水平和全身糖耐量受损 但不循环(体重增加对照)。此外,AT特异性胰岛素信号被消除, 体重循环小鼠。在研究结束时,AT中的巨噬细胞数量没有变化 在数量和表型上。然而,ATT的数量和多个TH 1相关的 基因在体重循环小鼠的AT中显著增加。这些数据证明 体重循环在AT中诱导了有效的T细胞驱动的适应性免疫应答,并表明 体重循环实际上诱导了二次适应性免疫反应。因此,总体假设 这种应用的一个重要方面是:体重循环导致加速的次级适应性免疫 这一反应加剧了AT的炎症反应,导致局部和全身胰岛素抵抗。 这一假设将在以下3个目标进行检验:1)确定体重循环是否会改变 ATT表型和功能; 2)确定体重循环是否诱导二次免疫应答 3)确定体重循环是否调节调节性T细胞(Treg)表型, 功能

项目成果

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Alyssa H Hasty其他文献

Alyssa H Hasty的其他文献

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{{ truncateString('Alyssa H Hasty', 18)}}的其他基金

Vanderbilt FIRST - Elevating Excellence and Transforming Institutional Culture
范德比尔特第一 - 提升卓越水平并转变机构文化
  • 批准号:
    10664626
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Faculty Development Core
教师发展核心
  • 批准号:
    10664628
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
BLRD Merit Review Research Career Scientist (RCS) Award (IK6)
BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)
  • 批准号:
    10373035
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Merit Review Research Career Scientist (RCS) Award (IK6)
BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)
  • 批准号:
    10221206
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Merit Review Research Career Scientist (RCS) Award (IK6)
BLRD 优异评审研究职业科学家 (RCS) 奖 (IK6)
  • 批准号:
    10618157
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Adipose Macrophage Iron Handling
脂肪巨噬细胞铁处理
  • 批准号:
    10624942
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Adipose Macrophage Iron Handling
脂肪巨噬细胞铁处理
  • 批准号:
    10164771
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Adipose Macrophage Iron Handling
脂肪巨噬细胞铁处理
  • 批准号:
    10415905
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Adipose Macrophage Iron Handling
脂肪巨噬细胞铁处理
  • 批准号:
    10018029
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Adipose Macrophage Iron Handling
脂肪巨噬细胞铁处理
  • 批准号:
    10181590
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

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