| Title: | Proteomic Signatures of Ectopic Fat Distribution: Tissue-Specific Drivers and Clinical Implications |
| Journal: | Med Research |
| Published: | 6 Jul 2026 |
| DOI: | https://doi.org/10.1002/mdr2.70078 |
Publication 20423
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Abstract
ABSTRACT Ectopic fat deposition is a major risk factor for cardiometabolic diseases, but its systemic molecular drivers and disease associations remain poorly understood, owing to the reliance on correlation studies, a single-organ perspective, and limited disease coverage. Plasma proteomic data (1454 proteins) and multi-organ MRI from 666 UK Biobank participants were integrated. A knockoff-based causal inference framework was applied to identify plasma proteins with putative causal effects on fat accumulation in the liver, pancreas, skeletal muscle, and pericardium. Tissue-specific machine learning models, functional enrichment analysis and systematic assessment of associations with 70 diseases were performed. Results showed that ectopic fat distribution varied substantially across tissues. Plasma proteome-based machine learning effectively predicted fat content across multiple organs, with a consistent performance hierarchy in both regression and classification tasks: liver ( R 2 = 0.74, AUC = 0.94) > pancreas > muscle > pericardium ( R 2 = 0.20, AUC = 0.67). Causal inference identified 94 organ-specific driver proteins, encompassing regulators of metabolism, inflammation, and signaling. Among these, PLA2G1B emerged as the strongest driver for pancreatic fat; ERBB2 and IGFBP2 acted as key positive and negative regulators of liver fat, respectively; CA14 and muscle fat formed a clear negative feedback loop; pericardial fat was primarily driven by NCAM2 and TNFRSF10B. Enrichment analysis revealed distinct, tissue-specific biological programs: pancreatic fat was linked to angiogenesis and humoral immunity; liver fat was associated with cytokine activity and PI3K-Akt signaling; muscle fat was connected to BMP/TGF-β signaling and extracellular matrix organization. Prognostically, muscle fat broadly correlated with cardiometabolic, neurological, and digestive diseases; liver fat was strongly linked to diabetes and hypertension; pancreatic fat was associated with metabolic conditions including diabetes and liver disease. Ectopic fat accumulation is driven by tissue-specific molecular mechanisms with distinct disease associations. This causal proteomic atlas provides novel regulatory circuits and protein targets, advocating for tissue-targeted diagnostic and therapeutic strategies. </p>
10 Authors
- Bing Zhang
- Fen Yang
- Xingji Lian
- Jie He
- Shuijin Huang
- Mingjuan Fan
- Yin Liang
- Jiaqiang Huang
- LongYan Yin
- Hong Wang
1 Application
| Application ID | Title |
|---|---|
| 109828 | Association Between Ultraprocessed Food Consumption and Risk of Incident CKD: A Cross-sectional and Prospective Analysis in the UK Biobank |
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