Adipocyte development and insulin resistance

脂肪细胞发育和胰岛素抵抗

• 批准号: 7733953
• 负责人: Vipul Periwal
• 金额: $ 10.34万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733953
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Age; Animals; Apoptosis; Behavior; Biopsy; Cell Count; Cell Size; Cells; Cessation of life; Characteristics; Chick Embryo; Classification; Condition; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Diet; Distant; Embryonic Development; Energy Intake; FVB Mouse; Fatty acid glycerol esters; Genetic; Glucose; Goals; Growth; Hand; Hepatic; Human; Hyperplasia; Hypertriglyceridemia; Hypertrophy; Hypoglycemia; Inbred Strains Mice; Individual; Insulin; Insulin Resistance; Lipids; Literature; Measures; Metabolic; Microscopic; Modeling; Mouse Strains; Mus; Obesity; Organism Strains; Oryctolagus cuniculus; Phenotype; Physiological; Process; Property; Range; Rate; Relative (related person); Reporting; Resistance; Role playing therapy; Signaling Molecule; Staging; Standards of Weights and Measures; Study models; Time; Tissues; Transgenic Mice; Triglycerides; Week; Weight; Wistar Rats; Zucker Rats; adipocyte differentiation; adipokines; cell growth; concept; in vivo; insight; insulin secretion; interest; mathematical model; research study; response; size

Obesity is an enlargement of adipose tissue to store excess energy intake. Hyperplasia 1(cell number increase) and hypertrophy (cell size increase) are two possible growth mechanisms. Adipose tissue obesity phenotypes are influenced by diet as well as genetics, or by their interaction. There is an extensive literature on adipose tissue growth in normal and abnormal development, characterizing the state of the tissue in terms of the mean cell size and cell number. Hyperplastic growth appears only at early stages in adipose tissue development. Hypertrophy occurs prior to hyperplasia to meet the need for additional fat storage capacity in the progression of obesity. However, it has proven difficult to understand how diet and genetics specifically affects hyperplasia and/or hypertrophy of adipose cells, because of limited data about adipose tissue growth. Beyond these studies, it has recently become possible to measure cell-size distributions precisely. This detailed information, compared with the mean cell size and total cell number, can be used to compute many size-related quantities that permit a finer characterization of the adipose tissue growth process. Cumulants of the cell-size distribution can be used to compute other physiological quantities such as the volume-weighted mean cell size. The cell-size distribution can be used to estimate total cell number within a fat pad from its mass. Furthermore, it is believed that some specific metabolic properties, e.g., insulin resistance and adipokine secretion, depend on the precise cell-size distribution rather than the mean cell size. Indeed, several studies have addressed the change of the size distribution of adipose cells under various conditions in chick embryo development, lean and obese Zucker rats, partially lipectomized Wistar rats, rabbit biopsy, and human adipose tissue. These studies focused only on the static differences between cell-size distributions under different conditions. However, cross-sectional static cell-size distributions for a range of snapshots of animal development can be used to deduce the dynamics of adipose tissue growth, if we can appropriately analyze the snapshots with the help of mathematical modeling. Given present technical limitations, this may be the best available approach to an understanding of in vivo adipose tissue growth, although a recent experiment has observed lipid accumulation in lipid droplets of adipose cells. To address genetic and dietary effects on the dynamic process of adipose tissue growth, we obtained cell-size distributions of epidydimal fat of obesity-resistant FVB/N (hereafter FVB) and obesity-prone C57Bl/6 (C57) mouse strains under standard chow and high-fat diets. The C57 mouse is the best characterized model of diet-induced obesity, and the FVB mouse is a preferable model for generating transgenic mice. These two commonly-used inbred mouse strains are genetically quite distant, and they have distinct metabolic phenotypes: Compared with FVB mice, C57 mice have low circulating triglyceride levels and increased triglyceride clearance; FVB mice are characterized by relatively higher hepatic insulin resistance, counter-regulatory response to hypoglycemia, and reduced glucose-stimulated insulin secretion; FVB mice are also known to be relatively lean since they appear to be less responsive to high-fat diet than C57 mice. However, the development of diet-induced obesity in these two strains has not been formally compared. In this study, we developed a mathematical model describing the change of the cell-size distribution as a function of the epidydimal fat pad mass to analyze quantitatively the dynamic characteristics that depend on genetics and/or diet. The model of adipose tissue growth describes how many new cells are formed, how each cell grows depending on its size, and how lipid turnover leads to size fluctuations that cause a spreading in the cell-size distribution. As the epidydimal fat pad mass increases, the cell-size distribution changes in a systematic manner depending on both genetics and diet. Comparing experimental results with the theoretical growth model, we found that hypertrophy is strongly correlated with diet. Hyperplasia, on the other hand, is initially dependent on genetics but is also affected by diet. Our central finding is that hyperplasia and hypertrophy of adipose cells in the epidydimal fat pad is a function of the fat pad mass, even though it may take individual animals different time periods to reach a given fat pad mass. Therefore, adipose tissue growth, represented as changes of the cell-size distribution, can be systematically modeled as a growth process with respect to fat pad mass increase; this may reflect a correlation between fat pad mass and the secretion of adipokines and other signaling molecules controlling adipose tissue growth. Accordingly, it should be noted that the rates in our model are not the usual rates per unit time increase but rates per unit mass increase. Thus, several rates in the model had larger values for animals on a chow diet than for those on a high-fat diet. However, if these rates are converted to the usual rates per unit time increase, they had larger values for the high-fat diet, because it takes less time to effect a unit increase inthe fat pad mass from larger, and more numerous, cells on a high-fat diet than to effect an increase of the same magnitude from smaller, and fewer, cells on a chow diet. It has been suggested that when obesity progresses, hypertrophy of adipose cells occurs early, and then triggers hyperplasia. Our study showed that new cell recruitment increases exponentially as fat pad mass increases. Hypertrophy of adipose cells is the main contributor to fat pad mass increase, whereas hyperplasia does not contribute much to this increase because it occurs in small cells that have a much smaller volume of fat stored. Therefore, our model naturally embodies the concept that hyperplasia is affected by the hypertrophic growth of cells. On the other hand, there have been reports that hyperplasia of adipose cells occurs only at early development stages; hence, there is no new cell recruitment at late stages even under obesogenic conditions. It may be the case that the age of the animals in our study (6 weeks old) allows the occurrence of hyperplasia. The model developed here may give microscopic insights into the size-dependent growth of adipose cells that cannot be addressed by static cross-sectional studies. We found specific properties of the size-dependent cell growth: the lower critical size, initializing lipid accumulation with enough lipid transporters, did not depend on diets in two mouse strains, whereas the upper critical size, limiting the cell growth with an extraordinary size, was enlarged on a high-fat diet. It may be of interest to see if these results can be generalized to other strains and organisms. In the tissue growth model, we included the recruitment of new cells and the growth of existing cells, but not the death of old cells, because the model was consistent with the data without the apoptosis of adipose cells. One recent study has reported that there is a turnover of human fat cells on a ten year time scale. Cell turnover may be irrelevant within the twelve week period of our study, but the model may need enhancement when it is applied to other fat depots that have functional differences, and to other species such as human.

肥胖是脂肪组织的扩大，以存储多余的能量摄入。增生1（细胞数增加）和肥大（细胞尺寸增加）是两个可能的生长机制。脂肪组织肥胖表型受饮食和遗传学的影响或它们的相互作用。关于正常和异常发育中脂肪组织生长的广泛文献，以平均细胞大小和细胞数来表征组织的状态。 增生生长仅在脂肪组织发育的早期才出现。 肥大发生在增生之前，以满足肥胖进展中额外脂肪储存能力的需求。然而，事实证明，由于有关脂肪组织生长的数据有限，因此很难理解饮食和遗传学如何特别影响脂肪细胞的增生和/或肥大。 除了这些研究之外，最近还可以精确地测量细胞大小的分布。与平均细胞大小和总细胞数相比，该详细信息可用于计算许多与尺寸相关的数量，以更细化的脂肪组织生长过程的表征。 细胞大小分布的累积物可用于计算其他生理量，例如体积加权平均细胞大小。细胞大小的分布可用于从其质量中估算脂肪垫内的总细胞数。此外，人们认为某些特定的代谢特性，例如胰岛素抵抗和脂肪因子分泌，取决于精确的细胞大小分布，而不是平均细胞大小。实际上，一些研究已经解决了在雏鸡胚胎发育，瘦肉和肥胖的扎克大鼠，部分脂肪切除的Wistar大鼠，兔活检和人类脂肪组织的各种条件下脂肪细胞在各种条件下的尺寸分布的变化。这些研究仅关注不同条件下细胞大小分布之间的静态差异。但是，如果我们可以在数学建模的帮助下适当地分析快照，则可以使用一系列动物发育快照的横截面静态细胞大小分布来推断脂肪组织生长的动力学。鉴于目前的技术局限性，这可能是了解体内脂肪组织生长的最佳方法，尽管最近的实验已经观察到脂肪细胞脂质液滴中的脂质积累。 为了解决对脂肪组织生长动态过程的遗传和饮食影响，我们获得了耐肥胖症的FVB/N（以下称FVB）和肥胖症的C57BL/6（C57）小鼠菌株的细胞大小分布（以下是FVB）。 C57小鼠是饮食诱导的肥胖症的最佳特征模型，而FVB小鼠是生成转基因小鼠的可取模型。这两种常用的杂交小鼠菌株在遗传上非常遥远，它们具有独特的代谢表型：与FVB小鼠相比，C57小鼠的甘油三酸酯水平较低，甘油三酸酯清除率增加； FVB小鼠的特征是相对较高的肝胰岛素抵抗，对低血糖的反应和葡萄糖刺激的胰岛素分泌减少。 FVB小鼠也相对较瘦，因为它们对高脂饮食的反应较低，而不是C57小鼠。但是，尚未正式比较这两种菌株中饮食引起的肥胖症的发展。在这项研究中，我们开发了一个数学模型，该数学模型描述了细胞大小分布的变化，这是附属脂肪垫质量的函数，以定量分析依赖遗传学和/或饮食的动态特征。脂肪组织生长的模型描述了形成了多少新细胞，每个细胞如何根据其大小而生长，以及脂质周转如何导致大小波动，从而导致细胞大小分布中扩散。随着附属脂肪垫质量的增加，细胞大小的分布会根据遗传学和饮食而系统地变化。将实验结果与理论生长模型进行比较，我们发现肥大与饮食密切相关。另一方面，增生最初取决于遗传学，但也受饮食影响。 我们的中心发现是，脂肪细胞在附属脂肪垫中的增生和肥大是脂肪垫质量的函数，即使可能需要单个动物的不同时间段才能达到给定的脂肪垫质量。因此，脂肪组织的生长表示为细胞大小分布的变化，可以系统地建模为相对于脂肪垫质量增加的生长过程。这可能反映了脂肪垫质量与脂肪因子的分泌与控制脂肪组织生长的其他信号分子之间的相关性。 因此，应该注意的是，我们模型中的速率不是单位时间的通常率增加，而是单位质量增加的速率。因此，该模型中的几个速率比在高脂饮食中的动物具有更大的动物价值。但是，如果将这些速率转换为单位时间时间的常规速率增加，则它们的高脂饮食值较大，因为在高脂饮食中，脂肪垫质量增加的脂肪垫质量增加所需的时间要少于高脂饮食中的细胞所花费的时间比较小的较小和较少的细胞在高脂饮食中增加相同的幅度。 有人提出，当肥胖症进展时，脂肪细胞的肥大会较早发生，然后触发增生。我们的研究表明，随着脂肪垫质量的增加，新的细胞募集会呈指数增加。脂肪细胞的肥大是导致脂肪垫质量增加的主要因素，而增生对这种增加并没有太大贡献，因为它发生在储存脂肪量较小得多的小细胞中。因此，我们的模型自然体现了增生受细胞肥大生长影响的概念。另一方面，有报道称脂肪细胞的增生仅在早期发育阶段发生。因此，即使在肥胖状态下，也没有新的细胞募集。可能是我们研究中动物的年龄（6周龄）允许发生增生。 此处开发的模型可能会提供微观的见解，以了解无法通过静态横截面研究来解决脂肪细胞的尺寸依赖性生长。我们发现了依赖大小的细胞生长的特定特性：较低的临界大小，用足够的脂质转运蛋白初始化脂质积累，并不依赖两种小鼠菌株中的饮食，而在高脂饮食上限制了具有非凡大小的上部临界大小，限制了细胞的生长。查看这些结果是否可以推广到其他菌株和生物可能会很感兴趣。 在组织生长模型中，我们包括了新细胞的募集和现有细胞的生长，而不是旧细胞的死亡，因为该模型与没有脂肪细胞凋亡的数据一致。最近的一项研究报告说，人类脂肪细胞的营业额是十年的时间范围。在我们研究的十二周期间，细胞更新可能无关紧要，但是当将其应用于具有功能差异的其他脂肪库以及其他物种（例如人类）时，该模型可能需要增强。