Non-invasive, longitudinal assessment of adipocyte size during the pathogenesis of type 2 diabetes

2 型糖尿病发病过程中脂肪细胞大小的非侵入性纵向评估

• 批准号: 10453201
• 负责人: Scott Charles Beeman
• 金额: $ 10.73万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453201
• 关键词: Adipocytes; Adipose tissue; Biopsy; Complement; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Ensure; Fatty acid glycerol esters; Flowcharts; Foundations; Funding; Goals; Gold; High Fat Diet; Histologic; Human; Hypertrophy; Hypoxia; In Situ; Inflammation; Insulin Resistance; Laboratory Study; Link; Lipids; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Methods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathway interactions; Pre-Clinical Model; Research; Rodent; Visceral; Work; base; clinically translatable; diet-induced obesity; experimental study; imaging modality; improved; in vivo; insight; insulin sensitivity; mouse model; resistance mechanism; standard measure; success; systemic inflammatory response; tissue oxygenation; tool

PROJECT SUMMARY The long-term goal of this work is to resolve the entirety of the “hypoxia-driven insulin resistance mechanism”, a hypothesized pathway to type 2 diabetes which starts with obesity, which causes adipocyte hypertrophy, which causes adipose hypoxia, which causes systemic inflammation, which ends in insulin resistance. This work is a direct expansion of the funded K01 proposal “MR Adipose-O2 Quantification and the Hypoxia-Driven Insulin Resistance Hypothesis” in which a magnetic resonance imaging (MRI)-based method for non-invasive quantifications of adipose oxygenation was developed and applied to interrogate the mechanistic relationship between adipose hypoxia, inflammation, and insulin resistance. Here, we aim to expand this research by non- invasively investigating the hypothesized link between obesity and adipose hypoxia - adipocyte hypertrophy. Insulin resistance is tightly linked to obesity, however, the pathogenic mechanisms linking obesity and insulin resistance are not well understood. One hypothesized pathway to insulin resistance is driven by adipose tissue hypoxia, wherein adipose tissue hypoxia initiates adipose tissue inflammation and, ultimately, systemic insulin resistance. Still, the hypothesized mechanistic link between adipose tissue hypoxia and obesity – adipocyte hypertrophy – has not yet been resolved. Quantification of adipocyte size during the hypoxia-driven pathogenesis of insulin resistance would provide evidence that adipocyte hypertrophy causes adipose hypoxia and would thus be a major advance towards a mechanistic understanding of how obesity leads to insulin resistance. The study of the pathogenesis of insulin resistance would benefit from a non-invasive method to quantify adipocyte size. Currently, the study of adipocyte size is limited by its reliance on invasive biopsy. Such methods all but preclude: (i) the study of visceral adipocytes, which have shown the strongest link to inflammation and insulin resistance but must be accessed via surgery, and (ii) serial measurements of adipocyte size on a single region of fat, which would greatly improve the mechanistic understanding of how obesity leads to insulin resistance. Diffusion MRI provides a means to these ends; in principle, diffusion MRI can be used to non- invasively measure adipocyte size based on the restricted diffusion of lipid within the adipocyte. Here we present data supporting this notion. This non-invasive, longitudinal MRI-based method will: (i) complement, and eventually replace, the current gold-standard biopsy-based methods for measuring adipocyte size and (ii) provide unique insight into the pathogenesis of insulin resistance in the form of longitudinal and in situ measurements of adipocyte size as a function of obesity, insulin sensitivity, and therapy. The Aims of this work are to: (i) Validate our non-invasive diffusion MRI method for quantifying adipocyte size in vivo and (ii) quantify adipocyte size during the healthy and pathogenic expansion of visceral white adipose and comparing these measures against those of adipose oxygenation, inflammation, and insulin sensitivity.

项目摘要 这项工作的长期目标是解决整个“缺氧驱动的胰岛素抵抗机制”， 2型糖尿病的假设途径始于肥胖，导致脂肪细胞肥大， 导致脂肪缺氧，引起全身炎症，最终导致胰岛素抵抗。这项工作是一个 直接扩展受资助的K 01提案“MR脂肪-O2定量和低氧驱动的胰岛素 阻力假说”，其中基于磁共振成像（MRI）的方法用于非侵入性 脂肪氧合的定量被开发并应用于询问机械关系 脂肪缺氧炎症和胰岛素抵抗之间的联系在这里，我们的目标是通过非- 侵入性研究肥胖和脂肪缺氧-脂肪细胞肥大之间的假设联系。 胰岛素抵抗与肥胖密切相关，然而，肥胖与胰岛素相关的致病机制 阻力还不太清楚。一种假设的胰岛素抵抗途径是由脂肪组织驱动的 缺氧，其中脂肪组织缺氧引发脂肪组织炎症，并最终引发全身胰岛素 阻力尽管如此，脂肪组织缺氧和肥胖之间的假设机制联系-脂肪细胞 肥大-尚未得到解决。缺氧驱动发病过程中脂肪细胞大小的定量 胰岛素抵抗的增加将提供证据表明脂肪细胞肥大导致脂肪缺氧， 是对肥胖如何导致胰岛素抵抗的机械理解的重大进展。 一种无创性的定量方法将有助于胰岛素抵抗发病机制的研究 脂肪细胞大小目前，脂肪细胞大小的研究受到其对侵入性活检的依赖的限制。此类方法 几乎排除了：（i）内脏脂肪细胞的研究，其显示出与炎症的最强联系， 胰岛素抵抗，但必须通过手术访问，和（ii）脂肪细胞大小的一个单一的系列测量 这将大大提高对肥胖如何导致胰岛素的机械理解 阻力弥散MRI为这些目的提供了一种手段;原则上，弥散MRI可用于非- 基于脂肪细胞内脂质的受限扩散侵入性地测量脂肪细胞大小。我们在此报告了 数据支持这一观点。这种非侵入性的、基于纵向MRI的方法将：（i）补充， 最终取代目前用于测量脂肪细胞大小的基于金标准活检的方法，以及（ii） 以纵向和原位的形式提供了对胰岛素抵抗发病机制的独特见解， 测量脂肪细胞大小作为肥胖、胰岛素敏感性和治疗的函数。 这项工作的目的是：（i）验证我们的非侵入性扩散MRI方法定量脂肪细胞的大小， 和（ii）在内脏白色脂肪的健康和致病性扩张期间量化脂肪细胞大小， 将这些指标与脂肪氧合、炎症和胰岛素敏感性指标进行比较。