Adipocyte development and insulin resistance

我们的假设是细胞大小依赖于细胞 死亡是改变饮食条件下脂肪组织重塑的重要组成部分。 在哺乳动物中，脂肪要么被利用，要么被储存。因此，我们假设一种功能障碍 脂肪组织生长可能是外周胰岛素抵抗的关键因素。脂肪组织 生长需要脂肪前体细胞的招募和发展，但几乎不需要 已经知道了体内的这些过程。在这项研究中，脂肪细胞大小的概率分布 在两只Zucker FA/FA大鼠的151天和163天内，从四周起使用 从动物身上获取皮下(腹股沟)脂肪组织的显微活检。这些纵向的 对概率分布进行了分析，以评估周期性现象的概率。脂肪 这种品系的大鼠的组织生长表现出惊人的时间周期，约为55天。 我们提出了一个简单的周期性模型，其中PPAR信号是由脂质中的De#64257；Cit驱动的 摄取能力导致新脂肪细胞的周期性募集。这个模型预测到 观察期将取决于饮食。我们正在与库什曼实验室合作 以获得验证这一假说的数据。 噻唑烷二酮类(TZD)是胰岛素增敏药物。它们有多种机制 作为核受体过氧化物酶体增殖物激活受体γ的配体的作用 (PPAR&947；)一个特别有趣的作用是对脂肪组织的作用。假设TZD 包括有限持续时间的重复治疗的方案可能会改善胰岛素 敏感性值得研究。Zucker肥胖大鼠是一个研究得很好的肥胖模型。我们治疗了 三只每天服用罗格列酮的Zucker肥胖大鼠，并保留三只作为对照。我们开发了 一种无需处死动物即可测量脂肪细胞大小分布的显微活检技术 我们可以随着时间的推移跟踪同一动物体内脂肪组织的发展，从而避免 在我们的初步实验中，动物间的差异很明显。我们发现TZD治疗 导致脂肪细胞体积增大，脂肪细胞数量增多。脂肪细胞数 增加似乎主要发生在治疗的头八天。是否可以使用 由于治疗而增加的脂肪储存可能会减轻脂肪毒性，从而促进胰岛素 敏感度。 脂肪组织动态地适应能量供应的过剩或稀缺。这个 储存能量的能力可以通过脂肪细胞数量或细胞内的变化来调节 尺码。我们 对该模型进行了扩展，以考虑来自霍尔组的关于细胞大小分布变化的新数据 由于饮食的改变，体重减轻不足。我们发现，小细胞体积的细胞凋亡和脂解可以 解释了体重减轻数据，但大细胞的细胞死亡发生在延长的 高脂肪饲料。在这项研究中，我们采取了 精确测量脂肪细胞大小概率分布的优势 持续高脂饮食对C57BL/6小鼠上述分布的影响 饮食和饮食不足从高脂肪饮食转变为正常饮食。我们检查了腹内 附睾部、肠系膜和腹膜后脂肪以及腹股沟皮下脂肪 脂肪储藏库的物种对饮食的反应。尽管高脂饮食会增加脂肪细胞和 最初增加电池数量，从长远来看，无法储存多余的能量。 大的脂肪细胞更容易细胞死亡，然而新生的脂肪细胞的数量 结节脂肪细胞也减少了，因为对脂肪的高需求缩小了 脂肪前体细胞的自我更新池。从高脂肪饮食向正常饮食转变 节食后，脂肪细胞缩小，细胞数量减少。与被动减少相比 在连续增重的细胞数中，细胞死亡主要发生在小细胞。 体重减轻，暗示了一种主动的机制来降低能量的潜在容量 储藏室。这些脂肪组织在体重增加和减少的情况下的变化在 四个肥沃的仓库。基于脂肪细胞大小分布的定量模型，我们 结论脂肪组织可以调节细胞的生长和死亡，取决于细胞的大小 适应储能需求。

Our hypothesis is that cell-size dependent cell death is an important component of adipose tissue remodeling under changing diet conditions. In mammals, fat must be either utilized or stored. Thus, we hypothesize that a dysfunction in adipose tissue growth may be a key factor in peripheral insulin resistance. Adipose tissue growth requires the recruitment and then the development of adipose precursor cells, but little is known about these processes in vivo. In this study, adipose cell-size probability distributions were measured in two Zucker fa/fa rats over a period of 151 and 163 days, from four weeks of age, using micro-biopsies to obtain subcutaneous (inguinal) fat tissue from the animals. These longitudinal probability distributions were analyzed to assess the probability of periodic phenomena. Adipose tissue growth in this strain of rat exhibits a striking temporal periodicity of approximately 55 days. We proposed a simple model for the periodicity, with PPAR signaling driven by a deficit in lipid uptake capacity leading to the periodic recruitment of new adipocytes. This model predicts that the observed period will be diet-dependent. We are collaborating with the Cushman laboratory to obtain data that tests this hypothesis. Thiazolidinediones (TZDs) are insulin-sensitizing drugs. They have multiple mechanisms of action as ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ ). A particularly interesting action is on adipose tissue. The hypothesis that a TZD regimen involving repeated treatments of limited duration may suffice for improvements in insulin sensitivity merits investigation. The Zucker fatty rat is a well-studied model of obesity. We treated three Zucker fatty rats with daily doses of rosiglitazone and kept three as controls. We developed a micro-biopsy technique to measure adipose cell-size distributions without killing the animal so we could follow the development of adipose tissue in the same animal over time, thus avoiding inter-animal variation evident in our preliminary experiments. We found that TZD treatment leads to adipose cell-size increase and adipose cell number increase. The adipose cell number increase appears to take place mostly over the first eight days of treatment. The availability of additional lipid storage due to treatment may alleviate lipotoxicity and thereby promote insulin sensitivity. Adipose tissue dynamically adapts to an excess or a scarcity of energy availability. The capacity of energy storage can be regulated by changes in adipose cell number or in cell size. We extended this model to take into account new data from the Hall group on changes in cell-size distributions under weight loss due to diet change. We find that apoptosis at small cell sizes and lipolysis can account for the weight loss data, but that cell death for large cells occurs for extended periods of high-fat feeding. In this study, we take advantage of precise measurements of adipose cell-size probability distributions to mathe- matically model changes in these distributions of C57BL/6 mice under continuous high-fat diet and under diet change from high-fat to regular diet. We examined intra-abdominal epididymal, mesenteric, and retroperitoneal fat as well as subcutaneous inguinal fat to see the fat-depot specific responses to diets. Although high-fat diet enlarges adipose cells and increases cell number initially, in the longer-term there is a failure to store excess energy. Large adipose cells are more susceptible to cell death, however the number of newly re- cruited adipose cells decreases as well because the high demand of differentiation shrinks the self-renewal pool of adipose precursor cells. Under diet change from high-fat to regular diet, adipose cells shrink and cell number decreases. Compared with the passive decrease of cell number under continuous weight gain, cell death mainly occurs at small cells under weight loss, suggesting an active mechanism to decrease the potential capacity of energy storage. These changes of adipose tissue under weight gain and loss were common in the four fat depots. Based on the quantitative modeling of adipose cell-size distributions, we conclude that adipose tissue can regulate cell growth and death depending on cell size to adjust to the demands of energy storage.