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Years of endurance exercise training remodel abdominal subcutaneous adipose tissue in adults with overweight or obesity

Nature Metabolism volume 6, pages 1819–1836 (2024)Cite this article

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Abstract

Abnormalities in the structure and metabolic function of abdominal subcutaneous adipose tissue (aSAT) underlie many obesity-related health complications. Endurance exercise improves cardiometabolic health in adults with overweight or obesity, but the effects of endurance training on aSAT are unclear. We included male and female participants who were regular exercisers with overweight or obesity who exercised for >2 years, and cross-sectionally compared them with well-matched non-exercisers with overweight or obesity. Here we show aSAT from exercisers has a higher capillary density, lower Col6a abundance and fewer macrophages compared with non-exercisers. This is accompanied by a greater abundance of angiogenic, ribosomal, mitochondrial and lipogenic proteins. The abundance of phosphoproteins involved in protein translation, lipogenesis and direct regulation of transcripts is also greater in aSAT collected from exercisers. Exploratory ex vivo experiments demonstrate greater angiogenic capacity and higher lipid-storage capacity in samples cultured from aSAT collected from exercisers versus non-exercisers. Regular exercise may play a role in remodelling aSAT structure and proteomic profile in ways that may contribute to preserved cardiometabolic health.

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Fig. 1: Study design.
Fig. 2: Structural and morphological comparison of aSAT between SED versus EX.
Fig. 3: Comparison of Mϕ and inflammatory pathway in aSAT and circulating inflammatory markers between SED versus EX.
Fig. 4: Comparison of aSAT proteomes by untargeted global or phosphoproteomics in well-matched SED versus EX.
Fig. 5: Comparison of aSAT proteomes by targeted immunoblots in well-matched SED versus EX.
Fig. 6: Comparison of aSAT remodelling capacity between EXev versus SEDev.

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Data availability

DAVID Knowledgebase v.2023q2 and reactome.db (v.1.88.0) were used for overrepresentation analysis. Global and phosphoproteomics data are hosted on GitHub (https://github.com/ahnchi/Comparing-Adipose-Tissue-). Source data are provided with this paper and can be found at https://doi.org/10.6084/m9.figshare.25998064 (ref. 91). All other datasets generated and analysed in this study are available from the corresponding author upon reasonable request.

Code availability

The R scripts used to preprocess and perform statistical analysis on the global/phosphoproteomics data are hosted on GitHub (https://github.com/ahnchi/Comparing-Adipose-Tissue-).

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Acknowledgements

We thank the study participants for their contributions. We also thank the Proteomics Resource Facility (PRF) at the University of Michigan for the excellent technical assistance, and all the members of the Substrate Metabolism Laboratory. This study was supported by The National Institutes of Health (grant nos. R01DK131724 and P30DK089503, J.F.H.) and the Marie Hartwig Research Award (University of Michigan, School of Kinesiology, J.F.H.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Substrate Metabolism Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

    Cheehoon Ahn, Tao Zhang, Gayoung Yang, Thomas Rode, Sophia J. Ghayur, Olivia K. Chugh & Jeffrey F. Horowitz

  2. Human Bioenergetics Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

    Pallavi Varshney

  3. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Hui Jiang

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Contributions

C.A., P.V. and J.F.H. designed the study. C.A., T.Z., G.Y., T.R., P.V., S.J.G., O.K.C., H.J. and J.F.H. contributed to data acquisition, analysis and interpretation. C.A. and J.F.H. drafted the work. All authors participated in revising the work. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Jeffrey F. Horowitz.

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Extended data

Extended Data Fig. 1 Comparison of tyrosine hydroxylase staining in aSAT between EX vs SED.

Representative images of Tyrosine hydroxylase in aSAT sections, and quantification of sympathetic innervation density (abundance of tyrosine hydroxylase positive staining per adipocyte). White scale bars indicate 100 µm. Sample sizes – SED: n = 15 and EX: n = 15. Data is expressed as mean ± SD.

Source data

Extended Data Fig. 2 Proteomics schematics and protein-protein interaction of predicted kinases in aSAT from EX and SED.

a) Schematic diagram providing an overview of the global proteomic/phosphoproteomic workflow. Created with Biorender. b) Protein-protein interaction of predicted kinases in aSAT rendered by Cytoscape. Sample sizes – SED: n = 8 and EX: n = 8.

Extended Data Fig. 3 Comparison of thermogenic, lipolytic, insulin signaling, and cellular signaling proteins in aSAT between SED vs EX.

a) Protein abundance of UCP1 and PRDM16. b) Ratio of phosphorylated ATGL to total ATGL and phosphorylated HSL to total HSL. c) Protein abundance of phosphorylated AKT (Thr308 and Ser473), total AKT, and ratio of phosphorylated AKT to total AKT. P = 0.0132 for pAKTT308:AKT. d) Protein abundance of phosphorylated STAT3 (Tyr705), total STAT3, and ratio of phosphorylated STAT3 to total STAT3. e) Representative blot images from SDS-page Western blot analysis (UCP1, PRDM16) and JESS immunoblot analysis (pAKTT308, pAKTS473, AKT, pSTAT3Y705, STAT3) are presented separately. Sample sizes – SED: n = 16 and EX: n = 16. Data is expressed as mean ± SD.

Source data

Extended Data Fig. 4 Schematics of ex vivo assays.

a) Schematic diagram outlining the workflow for the ex vivo angiogenesis assay. b) Schematic diagram outlining the workflow for ex vivo spheroid culture. Created with Biorender.

Supplementary information

Reporting Summary

Supplementary Data 1

List of primary antibodies and primers used for experiments.

Source data

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Fig. 2

Unprocessed western blots.

Source Data Fig. 5

Unprocessed western blots.

Source Data Extended Data Fig. 3

Unprocessed western blots.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 3

Statistical source data.

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Ahn, C., Zhang, T., Yang, G. et al. Years of endurance exercise training remodel abdominal subcutaneous adipose tissue in adults with overweight or obesity. Nat Metab 6, 1819–1836 (2024). https://doi.org/10.1038/s42255-024-01103-x

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  • DOI: https://doi.org/10.1038/s42255-024-01103-x

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