Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

Circadian misalignment due to night
work has been associated with
an elevated risk for chronic diseases. We investigated the effects
of circadian misalignment using shotgun protein profiling of peripheral
blood mononuclear cells taken from healthy humans during a constant
routine protocol, which was conducted immediately after participants
had been subjected to a 3-day simulated night shift schedule or a
3-day simulated day shift schedule. By comparing proteomic profiles
between the simulated shift conditions, we identified proteins and
pathways that are associated with the effects of circadian misalignment
and observed that insulin regulation pathways and inflammation-related
proteins displayed markedly different temporal patterns after simulated
night shift. Further, by integrating the proteomic profiles with previously
assessed metabolomic profiles in a network-based approach, we found
key associations between circadian dysregulation of protein-level
pathways and metabolites of interest in the context of chronic metabolic
diseases. Endogenous circadian rhythms in circulating glucose and
insulin differed between the simulated shift conditions. Overall,
our results suggest that circadian misalignment is associated with
a tug of war between central clock mechanisms controlling insulin
secretion and peripheral clock mechanisms regulating insulin sensitivity,
which may lead to adverse long-term outcomes such as diabetes and
obesity. Our study provides a molecular-level mechanism linking circadian
misalignment and adverse long-term health consequences of night work.