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Multi-omics correlates of insulin resistance and circadian function mapped directly from human serum
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  • Ngoc-Hien Du,
  • Flore Sinturel,
  • Nora Nowak,
  • Pauline Gosselin,
  • Camille Saini,
  • Idris Guessous,
  • Francois Jornayvaz,
  • Jacques Philippe,
  • Guillaume Rey,
  • Emmanouil Dermitzakis,
  • Renato Zenobi,
  • Charna Dibner,
  • Steven Brown
Ngoc-Hien Du
University of Zurich

Corresponding Author:[email protected]

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Flore Sinturel
Geneva University Hospitals
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Nora Nowak
ETH Zurich
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Pauline Gosselin
Geneva University Hospitals
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Camille Saini
Geneva University Hospitals
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Idris Guessous
Geneva University Hospitals
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Francois Jornayvaz
Geneva University Hospitals
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Jacques Philippe
Geneva University Hospitals
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Guillaume Rey
Geneva University Hospitals
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Emmanouil Dermitzakis
Geneva University Hospitals
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Renato Zenobi
ETH Zurich
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Charna Dibner
Geneva University Hospitals
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Steven Brown
University of Zurich
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Abstract

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.
27 Mar 2024Submitted to European Journal of Neuroscience
28 Mar 2024Assigned to Editor
28 Mar 2024Submission Checks Completed
03 Apr 2024Reviewer(s) Assigned