Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue
- 1The University of Manchester
Abstract
Glucocorticoids (GCs) are regulators of metabolism, yet how physiological GC exposure remodels adipose metabolism and its relationship with circulating biomarkers remains poorly understood. In a randomised cross-over study of individuals with primary adrenal insufficiency, near-physiological GC exposure was compared to withdrawal using integrated serum metabolomics, abdominal subcutaneous microdialysis metabolomics, and adipose tissue transcriptomics. GC exposure induced coordinated changes in adipose lipid and amino-acid metabolism. Pathway-level entropy analysis revealed GC-state-dependent transcriptional reorganisation, with concentrated organisation during exposure and diffuse organisation during withdrawal. Integrative hypergraph and topological analyses revealed GC-state-dependent reorganisation of circulating metabolite-adipose tissue relationships, with greater higher-order coordination during exposure. The circulating phenylalanine/kynurenine ratio discriminated GC state, showed the strongest shared connectivity to GC-regulated adipose networks, persisted at midnight and in an independent dose-response study, and exhibited circadian rhythmicity. These findings reveal dynamic GC regulation of adipose metabolism and identify a circulating biomarker with potential to guide personalised GC therapy.
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BibTeX
@misc{bennett2026higherorder,
title = {{Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue}},
author = {K. Bennett and D. Chantzichristos and T. Garner and P.-A. Jansson and A. Meyer and E. Doman and J. McQueen and P.-A. Svensson and O. Ragnarsson and G. Johannsson and A. Stevens},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757658},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757658v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue
AU - K. Bennett
AU - D. Chantzichristos
AU - T. Garner
AU - P.-A. Jansson
AU - A. Meyer
AU - E. Doman
AU - J. McQueen
AU - P.-A. Svensson
AU - O. Ragnarsson
AU - G. Johannsson
AU - A. Stevens
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757658
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757658v1
AB - Glucocorticoids (GCs) are regulators of metabolism, yet how physiological GC exposure remodels adipose metabolism and its relationship with circulating biomarkers remains poorly understood. In a randomised cross-over study of individuals with primary adrenal insufficiency, near-physiological GC exposure was compared to withdrawal using integrated serum metabolomics, abdominal subcutaneous microdialysis metabolomics, and adipose tissue transcriptomics. GC exposure induced coordinated changes in adipose lipid and amino-acid metabolism. Pathway-level entropy analysis revealed GC-state-dependent transcriptional reorganisation, with concentrated organisation during exposure and diffuse organisation during withdrawal. Integrative hypergraph and topological analyses revealed GC-state-dependent reorganisation of circulating metabolite-adipose tissue relationships, with greater higher-order coordination during exposure. The circulating phenylalanine/kynurenine ratio discriminated GC state, showed the strongest shared connectivity to GC-regulated adipose networks, persisted at midnight and in an independent dose-response study, and exhibited circadian rhythmicity. These findings reveal dynamic GC regulation of adipose metabolism and identify a circulating biomarker with potential to guide personalised GC therapy.
ER -