Multi‐omics correlates of insulin resistance and circadian parameters mapped directly from human serum

• Published in: The European journal of neuroscience Vol. 60; no. 7; pp. 5487 - 5504
• Main Authors: Du, Ngoc‐Hien, Sinturel, Flore, Nowak, Nora, Gosselin, Pauline, Saini, Camille, Guessous, Idris, Jornayvaz, François R., Philippe, Jacques, Rey, Guillaume, Dermitzakis, Emmanouil T., Zenobi, Renato, Dibner, Charna, Brown, Steven A.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.10.2024
• Subjects: Adult; Association analysis; Cell Line, Tumor; Circadian rhythm; Circadian Rhythm - physiology; Circadian rhythms; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Female; Genetic analysis; Genetic diversity; Genetic factors; Genome-Wide Association Study; Genomic analysis; GWAS; Humans; Insulin resistance; Insulin Resistance - physiology; Male; Metabolic disorders; Metabolomics; Metabolomics - methods; Middle Aged; Multiomics; Obesity - blood; Obesity - genetics; obesity and type 2 diabetes; serum metabolomics; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; obesity and type 2 diabetes; GWAS; circadian rhythms; insulin resistance; serum metabolomics
• DOI: 10.1111/ejn.16486
• ISSN: 0953-816X; 1460-9568

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome‐wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi‐omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells. We used a multi‐omic approach, combining genome wide association study (GWAS), metabolomics and lipidomics to uncover factors associated with circadian modifying effects exerted by sera from obese and/or type 2 diabetes patients. We found that sera from obese subjects carrying characteristics of insulin resistance caused period lengthening in U2OS cells. GWAS identified a genetic variant in March1 gene associated with insulin sensitivity that correlates with period lengthening effects.