3rd Edition of International Obesity and Metabolism Conference 2027

Abstract

Objectives: Obesity-driven metabolic disease is associated with compromised adipose tissue function. However, the molecular mechanisms underlying this dysfunction remain challenging to attribute to specific adipose cell populations, link mechanistically to inflammatory processes, and differentiate from pathways that normalize following weight loss. This study aimed to characterize obesity-associated molecular signatures in adipocytes and adipose microvascular endothelial cells at cell-type resolution, determine whether an obesity-like inflammatory environment can recapitulate adipose-resident cell dysfunction, and identify obesity-related programs showing evidence of reversal following bariatric surgery-induced weight loss.

Methods: We performed integrated untargeted proteomics and lipidomics on ex vivo adipocytes and adipose-resident endothelial cells from individuals across obese and lean BMI ranges. These findings were complemented by in vitro models of obesity-like inflammation and adipocyte-endothelial crosstalk, alongside analysis of paired subcutaneous adipose tissue samples collected before and after surgical weight loss. Results were validated using independent transcriptomic datasets and patient cohorts.

Results: Adipocytes from individuals with obesity demonstrated coordinated downregulation of mitochondrial energy metabolism pathways, including oxidative phosphorylation, TCA cycle activity, fatty acid β-oxidation, and branched-chain amino acid catabolism. These cells also exhibited altered lipid plasticity, characterized by triglyceride remodeling with relative depletion of shorter, more saturated species and enrichment of longer, more unsaturated species. Exposure to macrophage-conditioned media, simulating an obesity-like inflammatory environment, reproduced these alterations in vitro and diminished mitochondrial respiration. Endothelial cells displayed a distinct obesity-associated profile featuring attenuated cell-cycle signaling and elevated mitochondrial protein abundance. Analysis of paired adipose tissue following weight loss revealed broad restoration of mitochondrial and substrate-processing pathways, attenuated inflammatory signaling, and reciprocal triglyceride remodeling—with increases in shorter, more saturated species and decreases in longer-chain species—accompanied by recovery of lipogenic and β-oxidation enzymes. We also identified molecular features most strongly correlated with metabolic obesity phenotypes, including dyslipidemia, hypertriglyceridemia, and hyperglycemia.

Conclusions: Our cell-type-resolved, multi-context analytical framework reveals inflammation-responsive mitochondrial and lipid-handling dysfunction in adipocytes during obesity and delineates molecular programs that recover with weight loss. These findings provide mechanistic signatures relevant to understanding metabolic vulnerability in obesity.