biostudies-literatureXu PNCATS NIH HHSNIDDK NIH HHSNIA NIH HHSWake Forest School of MedicineNational Institutes of Health41-57.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC9852073biostudies-literatureUnknown14(1)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-specific rearrangements of gene regulations in response to insulin sensitivity. Integration of the gene co-expression 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 supplemental information.Cell systemsMulti-omic integration reveals cell-type-specific regulatory networks of insulin resistance in distinct ancestry populations.PMC9852073R01 DK090111U01AG046170U01 AG046170UL1 TR004419R01 DK118243R01 DK118287Wang MXu PLangefeld CDCivelek MDas SKSharma NKComeau MEWabitsch MZhang BfalseMulti-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-specific rearrangements of gene regulations in response to insulin sensitivity. Integration of the gene co-expression 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 supplemental information.2023-01-01T00:00:00Z2023 Jan2026-05-28T21:53:22.078Z2025-04-03T23:50:41.53ZS-EPMC98520733663095610.1016/j.cels.2022.12.005