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Genetics and Epigenetics

Genetic regulation of exosome biogenesis pathway in human adipose and muscle tissue and association with obesity and insulin resistance

International Journal of Obesity (2025)Cite this article

Subjects

Abstract

Background

Animal studies provide evidence of a link between exosome profile, obesity and insulin resistance (IR). Although it is known that exosomes mediate cell-cell communication via their macromolecular cargo, the genetic factors regulating exosomes in humans are largely unknown.

Methods

Leveraging genome-wide expression and genotype data from the African American Genetics of expression and Metabolism (AAGMEx) cohort, we focused on 262 genes in “Exosome pathway”, curated by us, to examine the relationship of the expression of these genes with IR and obesity and tested the role of single nucleotide polymorphisms (SNPs) in determining the variability in the expression of these genes in adipose and muscle tissue. Publicly available gene expression data on European ancestry individuals, genome-wide association studies (GWAS), and bioinformatic approaches were used to validate the role of obesity-associated genetic variants in regulating exosome pathway genes.

Results

Transcript levels of 96 and 15 exosome pathway genes were associated with gluco-metabolic traits (BMI and insulin sensitivity) in adipose and muscle tissue, respectively. Data also suggest transancestral replication of association. The cis-expression quantitative trait (cis-eQTL) analysis of exosome pathway genes identified 45 and 65 cis-eGenes in adipose and muscle tissue, respectively. Expression of a subset of 26 cis-eGenes in adipose was also associated with gluco-metabolic traits. Based on combined SNP-to-gene-linking analysis 35 and 82 adipose expressed exosomal genes (e.g. AHNAK, RAP2A) were identified as target genes for gluco-metabolic trait-associated SNPs in GWAS catalogue and UKBB GWAS datasets, respectively.

Conclusions

The expression of exosome pathway genes in adipose and muscle tissue are associated with obesity and IR, and expression of a subset of these genes are determined by SNPs. Furthermore, analysis of target genes of GWAS identified gluco-metabolic trait-associated SNPs suggests that a subset of these SNPs is potentially involved in causing obesity and related gluco-metabolic diseases, likely by modulating exosome biogenesis.

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Fig. 1: Expression of “exosome pathway” genes are correlated with obesity and gluco-metabolic traits.
Fig. 2: Expression of a subset of obesity and gluco-metabolic traits correlated “exosome-pathway” genes are genetically regulated.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Other information on data availability in public databases is included in the “Methods” section.

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Acknowledgements

We thank the investigators, staff, and participants of the AAGMEx cohort for their valuable contributions. Computations were performed using the Wake Forest University (WFU) High Performance Computing Facility (DEAC HPC). Clinical and genomic studies in the AAGMEx cohort were supported by National Institutes of Health NIH/NIDDK grant R01 DK090111 and R01 DK118243 (PI: SKD). The authors also thank the METSIM, FUSION, and other study investigators for publicly sharing their data.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Section on Endocrinology and Metabolism, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Swapan K. Das

  2. Center for Precision Medicine, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Swapan K. Das & Carl D. Langefeld

  3. Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Gagan Deep

  4. Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Gagan Deep

  5. Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Gagan Deep

  6. Department of Biostatistics and Data Science, Wake Forest University Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Mary E. Comeau & Carl D. Langefeld

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  1. Swapan K. Das
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  2. Gagan Deep
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  3. Mary E. Comeau
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Contributions

SKD conceptualized and designed the study; SKD collected data; MEC and CDL analyzed the data; SKD, GD, and CDL interpreted results; SKD wrote and finalized the manuscript; all authors read, edited, and approved the final manuscript.

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Correspondence to Swapan K. Das.

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Competing interests

GD is the founder of LiBiCo LLC, which has no influence or contribution to the work presented in this manuscript. Other authors have no conflict of interest.

Ethics approval and consent to participate

All participants in the AAGMEx cohort provided written informed consent under protocols approved by the Institutional Review Board (IRB) at Wake Forest University Health Sciences (Human Protocol: IRB00015775). The IRB reviewed all research involving humans to ensure that studies are conducted in accordance with the ethical standards put forward by the Belmont Report, and federal, state, and local regulations, and policies governing human research.

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Das, S.K., Deep, G., Comeau, M.E. et al. Genetic regulation of exosome biogenesis pathway in human adipose and muscle tissue and association with obesity and insulin resistance. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01933-z

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