While the link between circadian disruption and T2DM remains unclear, there is accumulating research suggesting that disrupted fasting/feeding circadian cycles are a key mediator of metabolic dysfunction ( 21). Consistently, genetic disruption of the core elements of the molecular clock (e.g., Arntl and Clock) in mice leads to characteristic features of T2DM such as hyperglycemia and loss of circadian regulation of glucose tolerance and insulin secretion ( 18– 20). Most notably, chronic circadian rhythm disruptions (CDs) are associated with increased incidence of metabolic diseases such as type 2 diabetes mellitus (T2DM) ( 14– 17). Circadian transcription factors coordinate expression of thousands of genes that orchestrate circadian rhythmicity and optimize regulation of essential cellular functions such as substrate metabolism, cell cycle, and mitochondrial function ( 8– 11).Īlthough the circadian system undoubtedly provides evolutionary advantage, modern lifestyle and work conditions impose temporal constraints that produce disruptions in daily light/dark, rest/activity, and fasting/feeding cycles, as seen in a large proportion of the population worldwide ( 1, 12, 13). This primary feedback loop is further modulated by secondary regulatory loops involving the nuclear hormone transcription factors REV-ERBα/β and RAR-related orphan receptor α and β (RORα/β) as well as the proline and acidic amino acid–rich basic leucine zipper (PAR bZIP) transcription factors: D site of albumin promoter binding protein (DBP), thyrotroph embryonic factor (TEF), and hepatic leukemia factor (HLF) ( 7). Once translated, PERIOD and CRYPTOCHROME proteins bind to the CLOCK:BMAL1 complex to repress their own transcription, thus completing the feedback loop ( 6). The core components of the primary feedback loop include transcriptional activators: brain muscle aryl nuclear translocase 1 (BMAL1) and its heterodimeric partner, circadian locomotor output cycles kaput (CLOCK), which bind to E-box elements in the promoters of their own repressor genes Period 1-3 ( Per1, Per2, and Per3) and Cryptochrome 1 and 2 ( Cry1 and Cry2) ( 6). This study provides mechanistic insights into circadian regulation of β cell function and corresponding beneficial effects of tRF in prevention of T2DM.Īt the cellular level, circadian rhythms are driven by cell-autonomous transcriptional-translational feedback loops. In contrast, restoration of fasting/feeding cycle prevented CD-mediated dysfunction by reestablishing circadian regulation of glucose tolerance, β cell function, transcriptional profile, and reestablishment of proline and acidic amino acid–rich basic leucine zipper (PAR bZIP) transcription factor DBP expression/activity. Results show that CD perturbs glucose homeostasis through disruption of pancreatic β cell function and loss of circadian transcriptional and epigenetic identity.

Here, we used an approach encompassing analysis of behavioral, physiological, transcriptomic, and epigenomic effects of CD and consequences of restoring fasting/feeding cycles through time-restricted feeding (tRF) in mice. While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates metabolic dysfunction. Circadian rhythm disruption (CD) is associated with impaired glucose homeostasis and type 2 diabetes mellitus (T2DM).

Abi time clock