Metabolomic and Proteomic Signatures of Circadian Syndrome by Metabolic Bariatric Surgery Status in QPHI Participants: A cross-sectional analysis

Abstract Background Circadian Syndrome (CircS) combines metabolic risk factors with sleep and depressive symptoms. Metabolic Bariatric surgery (MBS) improves several CircS components, but the molecular features associated with CircS after surgery remain poorly understood. This study examined plasma metabolomic and proteomic signatures of CircS according to MBS status among Qatar Precision Health Institute (QPHI) participants. Methods This cross-sectional study included QPHI participants with CircS classification and plasma metabolomic (n = 211; 62 MBS, 149 no-MBS) or proteomic (n = 148; 59 MBS, 89 no-MBS) data. CircS was defined by the presence of ≥ 4 of seven components: central obesity, elevated triglycerides, reduced HDL-cholesterol, elevated blood pressure, elevated blood glucose, short sleep duration, and depressive symptoms. Age- and sex-adjusted linear models were used to assess differential molecular abundance for two contrasts: (1) CircS vs. no-CircS within the MBS group and (2) CircS vs. no-CircS within the no-MBS group. Significance was determined using the Benjamini-Hochberg false discovery rate (FDR). Results Within the MBS group, CircS was significantly associated with higher levels of inosine 5′-monophosphate (IMP; log 2 FC = 2.94, p adj = 0.01) and keratin 18 (KRT18; log 2 FC = 1.25, p adj = 0.048). Within the no-MBS group, 12 metabolites, but no proteins, remained significant after FDR correction, primarily involving amino acid and phospholipid metabolism. Conclusions This multi-omics analysis reveals distinct molecular signatures of CircS according to MBS status. In participants with MBS, CircS was associated with alterations in purine metabolism (IMP) and an epithelial cell marker (KRT18). In contrast, the no-MBS group showed broader metabolic associations spanning amino acid and plasmalogen metabolism. These findings suggest that the molecular associations of CircS differ according to MBS status; given the cross-sectional design, independent longitudinal studies are needed to test whether MBS alters these pathways.