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.