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