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

项目总结 这项工作的长期目标是彻底解决“低氧驱动的胰岛素抵抗机制”，即 2型糖尿病的假想途径始于肥胖，肥胖会导致脂肪细胞肥大， 导致脂肪缺氧，引起全身炎症，最终导致胰岛素抵抗。这项工作是一项 K01建议“MR脂肪-O2量化与低氧驱动的胰岛素”的直接扩展 一种基于磁共振成像(MRI)的非侵入性治疗方法 脂肪氧合的量化被开发并应用于询问机制关系 脂肪缺氧、炎症和胰岛素抵抗之间的关系。在这里，我们的目标是扩大这项研究的非 侵入性地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，肥胖和胰岛素之间的致病机制 抵抗并没有得到很好的理解。脂肪组织是导致胰岛素抵抗的一条假想途径 低氧，其中脂肪组织低氧引发脂肪组织炎症，最终引发全身性胰岛素 抵抗。尽管如此，脂肪组织缺氧和肥胖之间假想的机制联系--脂肪细胞 肥大--尚未解决。低氧致病过程中脂肪细胞大小的定量研究 胰岛素抵抗将提供脂肪细胞肥大导致脂肪缺氧的证据，从而 这是对肥胖如何导致胰岛素抵抗的机械性理解的重大进步。 研究胰岛素抵抗的发病机制将得益于一种非侵入性的量化方法。 脂肪细胞大小。目前，脂肪细胞大小的研究受到对侵入性活检的依赖。这样的方法 几乎排除了：(I)对内脏脂肪细胞的研究，它与炎症和 胰岛素抵抗，但必须通过手术和(Ii)脂肪细胞大小的连续测量 脂肪区域，这将极大地提高对肥胖如何导致胰岛素的机制的理解 抵抗。弥散磁共振成像提供了一种达到这些目的的方法；原则上，扩散磁共振成像可以用于非 根据脂肪细胞内脂肪扩散的限制，侵入性地测量脂肪细胞的大小。在这里，我们呈现 支持这一观点的数据。这种基于纵向MRI的非侵入性方法将：(I)补充 最终取代目前以金标准活检为基础的脂肪细胞大小测量方法和(Ii) 以纵向和原位的形式对胰岛素抵抗的发病机制提供独特的见解 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磁共振方法，以定量脂肪细胞的大小 活体和(Ii)在内脏白色脂肪健康和病理性扩张期间脂肪细胞大小的量化 将这些指标与脂肪氧合、炎症和胰岛素敏感性的指标进行比较。

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.