Depot-specific molecular remodelling of human adipose tissue and liver following bariatric surgery revealed by longitudinal multi-omic profiling

Background Obesity and its complications, including metabolic dysfunction-associated steatotic liver disease, remain significant global health challenges. Bariatric surgery has established clinical benefits, but the mechanisms driving metabolic improvements are not clearly defined. Methods We undertook a randomised, prospective, longitudinal (1-year) study in women living with obesity to determine the impact of a low-calorie diet followed by bariatric surgery (individuals randomised to sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB)) on metabolic phenotype, including MASLD. We combined repeated clinical assessments with state-of-the-art imaging, dynamic meal testing and a multi-omic analysis (proteomic, metabolomic) from tissue (multiple adipose depots, liver) and blood. A control group without obesity underwent identical phenotyping and molecular analysis with the exception of no low-calorie diet. Results Obesity was associated with metabolic, proteomic and hepatic dysregulation. Bariatric surgery normalized non-invasive assessments of liver phenotype and was associated with reductions in body fat, notably in android as opposed to gynoid fat mass. This was paralleled by proteomic changes in abdominal, but not gluteal, adipose tissue. Proteomic and metabolomic analyses highlighted putative roles for all-trans-retinol dehydrogenase, lumican and androgenic steroids in the regulation of metabolic phenotype. Clinical or molecular outcomes were not significantly different between SG and RYGB. Conclusions These data highlight the differential impact of bariatric surgery on adipose tissue depots, and this is likely to be crucial in delivering metabolic benefit. Furthermore, the specific pathways and targets that have been identified offer the potential for therapeutic intervention.