Molecular metabolism · 2026
BMI-anchored transcriptomics uncovers oxidative and inflammatory poles of obesity heterogeneity.
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Yin-Yuan Su, Linnaeus Bundalian, Yin-Cheng Chen, Erind Gjermeni, Benedikt Gille, Sandy Richter, Mariami Jasaszwili, Sergio Eliseo Palma-Vera, Anne Hoffmann, Adhideb Ghosh, Christian Wolfrum, Matthias Blüher, Shahaf Peleg, Antje Garten, Diana Le Duc, Chen-Ching Lin
Аннотация
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.
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.