Diabetes and Metabolic Syndrome are Associated with Disruption of Biological Circadian Rhythms and Resetting by Feeding

Organisms developed circadian rhythms to align energy utilization with energy availability. The central clock is the suprachiasmatic nucleus (SCN) located within the hypothalamus and is set by light. Most major organs also contain circadian rhythms and these peripheral clocks can be independently set by other external cues. Feeding, for example, resets clock in the liver.  Dyssynchrony between the SCN and peripheral clocks leads to aberrant circadian rhythms that are associated with metabolic syndrome, a prediabetic condition.  More research is needed to elucidate dietary factors that reset the liver clock. We therefore investigated the impact of dietary iron on daily oscillations of glucose tolerance and insulin secretion in three month old C57BL/6J male mice fed diets containing 2000 (High, H), 500 (High-Normal, HN), or 35 (Low-Normal, LN) mg iron/kg chow. These results showed that mice fed LN diet maintained flexibility in insulin secretion when compared to the other groups. Using real time polymerase chain reaction we found a gradient in liver transcripts of the core clock components, with H fed mice having greater oscillations while LN fed mice had damped rhythms. These changes in rhythmicity were associated with significant changes in hepatic glucose production, which is a major determinant of blood glucose concentrations.  These results were recapitulated in HepG2 cells, a human hepatoma culture model, to further explore the mechanism of how iron is able to alter circadian rhythms. Our studies will lead to a better understanding of how metabolic parameters affect the increased risk of diabetes seen in shift workers.