Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue

Bennett, K.; Chantzichristos, D.; Garner, T.; Jansson, P.-A.; Meyer, A.; Doman, E.; McQueen, J.; Svensson, P.-A.; Ragnarsson, O.; Johannsson, G.; Stevens, A.

doi:10.64898/2026.10.08.757658

bioRxiv · 10.64898/2026.10.08.757658

Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue

Bennett, K.·Chantzichristos, D.·Garner, T.·Jansson, P.-A.·Meyer, A.·Doman, E.·McQueen, J.·Svensson, P.-A.·Ragnarsson, O.·Johannsson, G.·Stevens, A.

View original source ↗Export metadata ↓

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.

Explore related subjects

systems biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Bennett, K., Chantzichristos, D., Garner, T., Jansson, P.-A., Meyer, A., Doman, E., McQueen, J., Svensson, P.-A., Ragnarsson, O., Johannsson, G., Stevens, A.. 2026-10-09. Higher-Order Organization Links Circulating Metabolites to Glucocorticoid Action in Human Adipose Tissue. https://doi.org/10.64898/2026.10.08.757658

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Dietary fibre responses emerge through host-dietary regime interplay: Apple pectin modulates immune reactivity in adult zebrafish

Dietary fibres are rarely consumed independently. Instead, they form part of an overall diet that includes dietary fibres from different sources, in varying amounts and consumed under different feeding patterns. Here, we tested how dietary regimes containing apple pectin, oat {beta}-glucan, or cellulose shaped the host. We analysed gut microbiome composition by 16S rRNA sequencing, measured brain and intestinal SCFA profiles by targeted metabolomics, and assessed immunomodulation by measuring gene expression systemically in the blood and locally in the spleen, as well as intestinal enzyme activity. The dietary intervention was conducted for 12 weeks on adult female and male zebrafish (Danio rerio). Our results show that the gut microbial composition can be relatively stable across different dietary fibre exposure patterns yet still vary significantly between the sexes. Additionally, the effect of sex on the gut microbiome may become more evident when dietary fibres are administered at high dosages, but intermittently. Dietary fibre regimes can alter intestinal short-chain fatty acid profiles more readily than brain profiles, which show a stronger sexually dimorphic response. Interestingly, apple pectin modulated the zebrafish immune response through interactions dependent on the overall regime, tissue, sex, and host immune status. Notably, tissue il1b gene expression differed depending on how apple pectin was administered and the host's physiological state. Collectively, our study emphasises the highly context-specific effects of dietary fibres, shaped by the dynamic interplay between the overall dietary regime and intertwined host factors.

systems biology↗

bioRxiv2026

Co-transcriptomic network analysis of host-parasite interactions reveals genes underpinning parasite fitness

Interactions between parasites and their host organisms generate continuous variation in infection outcomes. Although dual transcriptome studies have demonstrated extensive molecular dialogues between interacting species, it is still unclear how natural variation in host and parasite gene regulatory networks and coordination between them contribute to diverse disease phenotypes. Here, we re-contextualized co-transcriptomes from recombinant inbred lines of the plant-parasitic root-knot nematode Meloidogyne hapla infecting Medicago truncatula host plants with relative measures of infection intensity as a proxy for parasite load. We used infection intensity to estimate interaction gradients on gene expression by calculating its covariance with transcript levels. Quantitative analyses of interaction gradients for host and parasite transcriptomes identified major differences in development-related transcriptional programs along the infection continuum. In addition, integrated network analyses connected host cell wall remodeling with parasite protein production and secretion. Silencing of candidate root-knot nematode genes reduced host galling and parasite reproductive fitness, providing experimental support for our network-derived predictions. Together, our findings present an integrated systems genetics framework connecting naturally occurring genetic variation to quantitative disease phenotypes.

systems biology↗

bioRxiv2026

Targeted proteomics informed by long-read RNA-sequencing reveals protein isoform expression associated with bone mineral density

The expanding catalog of sQTLs from projects like GTEx has established that genetic risk for complex traits is frequently mediated through RNA splicing. Yet it is generally unknown whether disease-associated splice events produce stable, distinct protein isoforms and whether they are functionally consequent. Even the deepest shotgun proteomics efforts only capture a minority of annotated splice events; isoform-specific peptides are systematically under-sampled by nature of being lower abundance and intrinsically harder to detect. Here, we implement a genetics-guided targeted mass spectrometry (MS) strategy to detect splice-derived protein isoforms prioritized by sQTL colocalization. Using internal standard parallel reaction monitoring (IS-PRM), we targeted 288 peptides corresponding to 166 putative BMD-associated isoforms in differentiating osteoprogenitor cells and patient-derived primary mesenchymal stem cells (MSCs). Targeted acquisition increased recovery of isoform-informative peptides relative to conventional DDA, rescued splice events that were undetected or sparsely sampled under global acquisition, and confirmed protein-level expression of genetically prioritized isoforms in clinical material. Together, this work establishes that targeted MS is a useful approach to support validation of protein expression in studies of the genetics of splicing.

systems biology↗