Multi-omic integration reveals cell-type-specific regulatory networks of insulin resistance in distinct ancestry populations

Our knowledge of the cell-type-specific mechanisms of insulin resistance remains limited. To dissect the cell -type-specific molecular signatures of insulin resistance, we performed a multiscale gene network analysis of adipose and muscle tissues in African and European ancestry populations. In adipose tissues, a comparative analysis revealed ethnically conserved cell-type signatures and two adipocyte subtype-enriched modules with opposite insulin sensitivity responses. The modules enriched for adipose stem and progenitor cells as well as immune cells showed negative correlations with insulin sensitivity. In muscle tissues, the modules enriched for stem cells and fibro-adipogenic progenitors responded to insulin sensitivity oppositely. The adipocyte and muscle fiber-enriched modules shared cellular-respiration-related genes but had tissue -spe-cific rearrangements of gene regulations in response to insulin sensitivity. Integration of the gene co -expres-sion and causal networks further pinpointed key drivers of insulin resistance. Together, this study revealed the cell-type-specific transcriptomic networks and signaling maps underlying insulin resistance in major glucose-responsive tissues. A record of this paper's transparent peer review process is included in the sup-plemental information.

Automated summary

This study conducted a multiscale gene network analysis of adipose and muscle tissues in African and European populations to reveal the cell-type-specific molecular signatures of insulin resistance. The research identified two adipocyte subtype-enriched modules and modules enriched for stem cells and fibro-adipogenic progenitors that showed opposite insulin sensitivity responses. The study also pinpointed key drivers of insulin resistance through the integration of gene co-expression and causal networks.