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

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 (2024). Multi‐omics correlates of insulin resistance and circadian parameters mapped directly from human serum. European Journal of Neuroscience, 60(7):5487-5504.

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Language:English
Date:1 October 2024
Deposited On:04 Nov 2024 12:18
Last Modified:31 Jan 2025 02:38
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0953-816X
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1111/ejn.16486
PubMed ID:39205434
Project Information:
  • Funder: Novartis Stiftung für Medizinisch-Biologische Forschung
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  • Funder: Fondation ISREC
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  • Funder: Vontobel-Stiftung
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  • Funder: Fondation Leenaards
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  • Funder: Vontobel-Stiftung
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  • Funder: Olga Mayenfisch Stiftung
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  • Funder: Novartis Stiftung für Medizinisch-Biologische Forschung
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  • Funder: Fondation Leenaards
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  • Funder: Fondation Ernst et Lucie Schmidheiny
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  • Funder: Jubiläumsstiftung von Swiss Life
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  • Funder: Velux Stiftung
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  • Funder: Krebsliga Schweiz
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  • Funder: Fondation ISREC
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

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