Role of adipose tissue cellular composition on healthy metabolism

我们研究的长期目标是确定有益改变的机制 脂肪组织的生理和细胞功能，它可以改善胰岛素信号功能，抑制 全身炎症，促进健康衰老。 对小鼠、大鼠和人类的几项研究表明，肥胖会导致胰岛素抵抗， 对寿命有负面影响。然而，我们对长寿的艾姆斯侏儒小鼠的研究表明， 生长激素缺乏的动物具有改变的脂肪组织功能， 而不考虑在衰老过程中肥胖的倾向。根据我们以前的研究，我们决心 发现高胰岛素敏感性、低炎症和健康衰老的机制。 我们提出的一般假设，即质量（细胞组成），而不是 大量的白色脂肪组织（WAT）调节高胰岛素敏感性， 全身炎症，促进健康衰老。 在我们提出的研究中，我们将（i）研究WAT驻留的Treg细胞是否有助于维持健康的免疫系统 通过促进间充质干细胞（MSC）自我更新平衡和低炎症，（ii）研究 Treg细胞耗尽对代谢和炎症的后果，（iii）阐明机制 负责df/df小鼠中脂肪来源的MSC的自我更新，以及（iv）确定 Treg细胞和MSCs对脂肪细胞内分泌功能的影响。 我们提出以下具体目标： 目标1.为了确定WAT驻留Treg细胞和MSC在胰岛素敏感性和炎症反应中的作用， 在衰老过程中df/df和N/df小鼠中的状态：（A）研究Treg细胞的扩增是否会促进自我更新 和（B）研究Treg细胞的消耗是否会对WAT驻留的MSC和健康的胰岛素敏感性产生影响， 对胰岛素敏感性、炎症和WAT驻留的MSC群体的自我更新的负面影响。 目标二。为了确定脂肪驻留和浸润性Treg细胞和MSC的分子机制， 调节脂肪细胞的内分泌活动。

The long-term goal of our research is to determine the mechanism responsible for beneficial alteration of the physiology and cellular function of adipose tissue, which improves insulin signaling function, suppresses systemic inflammation, and promotes healthy aging. Several studies with mice, rats, and humans have indicated that obesity causes insulin resistance and has negative effects on longevity. However, our studies with long-living Ames dwarf mice indicate that these growth hormone deficient animals have altered functions of adipose tissue that promote healthy phenotypes regardless of a predisposition to obesity during aging. Following our previous studies, we are determined to discover the mechanism responsible for high insulin sensitivity, low inflammation, and healthy aging. We propose the general hypothesis that the quality (cellular composition), and not quantity, of white adipose tissue (WAT) regulates high insulin sensitivity, protects against systemic inflammation, and promotes healthy aging. In our proposed studies we will (i) study whether WAT residing Treg cells help maintain a healthy immune balance and low inflammation by promoting mesenchymal stem cells (MSCs) self-renewal, (ii) investigate the consequences of Treg cells depletion on metabolism and inflammation, (iii) elucidate the mechanism responsible for self-renewal of adipose derived MSCs in df/df mice, and (iv) determine the regulatory role of Treg cells and MSCs on the endocrine function of adipocytes. We propose the following specific aims: Aim 1. To determine the role of WAT residing Treg cells and MSCs on insulin sensitivity and inflammatory status in df/df and N/df mice during aging: (A) investigate if expansion of Treg cells will promote self-renewal of WAT residing MSCs and healthy insulin sensitivity, and (B) study whether depletion of Treg cells will have a negative effect on insulin sensitivity, inflammation, and self-renewal of WAT residing MSCs populations. Aim 2. To determine the molecular mechanism by which fat-resident and infiltrating Treg cells and MSCs regulate the endocrine activity of adipocytes.