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Yin-Yuan, S.* ; Linnaeus, B.* ; Yin-Cheng, C.* ; Erind, G.* ; Benedikt, G.* ; Sandy, R.* ; Mariami, J.* ; Sergio Eliseo, P.V.* ; Hoffmann, A. ; Adhideb, G.* ; Christian, W.* ; Blüher, M. ; Shahaf, P.* ; Antje, G.* ; Diana, L.D.* ; Chen-Ching, L.*

BMI-anchored transcriptomics uncovers oxidative and inflammatory poles of obesity heterogeneity.

Mol. Metab. 114:102462 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: BMI remains the dominant clinical index of obesity, but does not resolve adipose molecular programs that distinguish metabolic resilience from vulnerability. METHODS: Among 1,479 available human visceral adipose RNA-seq profiles, 1,298 samples from individuals with BMI 30-60 were included in the primary modeling cohort. Using BMI as a phenotypic anchor, we fit a LASSO regression model to derive transcriptome-predicted BMI and applied the resulting BMI-anchored transcriptomic model to mouse selection lines with divergent obesity phenotypes. In humans, directional discordance between measured and predicted BMI was used to define transcriptome-derived metabolically healthy obesity-like (MHO-like) and metabolically unhealthy obesity-like (MUO-like) states and to characterize pathophysiologic variation beyond measured BMI. RESULTS: Model-selected genes converged on immune, metabolic, mitochondrial, growth, structural-remodeling, and proteostasis programs. Cross-species application showed that BMI-anchored transcriptomic scores more closely tracked adipose-tissue content than body-size condition factor, distinguishing lipid-anabolic and inflammatory features of obesity-prone DU6 mice from the oxidative-catabolic phenotype of DU6P mice characterized by increased muscle mass. Gene-level associations with the transcriptomic score mirrored DU6-associated expression changes, linking the cross-species axis to an obesity-vulnerable adipose state. In humans, MHO-like individuals showed enhanced mitochondrial energy-production programs and more favorable glycemic and lipid profiles, whereas MUO-like individuals showed stress-adaptive metabolic remodeling and greater cardiometabolic medication use. In a separate, non-overlapping validation cohort, projection onto the primary-cohort PCA space retained a signal associated with insulin resistance that remained essentially unchanged after adjustment for sex. CONCLUSIONS: These findings support a conserved adipose transcriptomic axis linking oxidative metabolic resilience to healthier obesity and lipid-inflammatory remodeling to metabolic vulnerability.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adipose Tissue Metabolism ; Adipose Transcriptomics ; Bmi-anchored Transcriptomic Model ; Cross-species Model ; Obesity ; Visceral Adipose Tissue
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 114, Heft: , Seiten: , Artikelnummer: 102462 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)