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.
