Post-translational modifications of core-clock factors can also regulate transcription (e.g., deacetylation of BMAL1 or PER2 by SIRT1 ). An additional level of circadian regulation exists with CRYs and PERs, which have been reported to bind independently of other core-clock factors to genomic sites enriched with Nuclear Receptor (NR) recognition motifs (response element, RE). In a secondary loop, Bmal1 is regulated by the repressor REV-ERBα and its opposing nuclear receptor RORα, which bind competitively to the shared element RORE, thus repressing or activating the transcription of the Bmal1 gene, respectively (reviewed in ). The phosphorylation of the repressors mediated by Casein Kinases 1 ( CK1ε and CK1δ) and AMPK directs these proteins to ubiquitin-mediated proteasomal degradation (which, for CRY1, is regulated by FBXL protein ratios). The negative limb proteins (PERs and CRYs) multimerize and inhibit CLOCK/BMAL1.
The mammalian circadian clock consists of transcription/ translation feedback loops in which the positive limb (CLOCK or NPAS2 and BMAL1) heterodimerizes and activates the transcription of downstream genes, including Per, Cry, Rorα and Rev-erbα. Collectively, a better knowledge of the mechanisms by which the circadian clock function can be compromised will lead to novel preventive and therapeutic strategies for obesity and other metabolic disorders arising from circadian desynchrony.Īdipose tissue circadian rhythm high-fat diet metabolism molecular clock nutrients obesity suprachiasmatic nucleus. Finally, we discuss the relay of environmental information by signal-dependent transcription factors to adjust the timing of gene oscillations. Here, we discuss some mechanisms responsible for diet-induced circadian desynchrony and consider the impact of nutritional cues in inter-organ communication, with a particular focus on the communication between peripheral organs and brain. This review illustrates the impact of genetically or environmentally induced molecular clock disruption (at the level of the brain and peripheral tissues) and the interplay between the circadian system and metabolic processes. Inappropriate timing of food intake and high-fat feeding also lead to disruptions of the temporal coordination of metabolism and physiology and subsequently promote its pathogenesis.
Evidence from animal genetic models and from humans under circadian misalignment (such as shift work or jet lag) shows that disruption of circadian rhythms contributes to the development of obesity and metabolic disease. Circadian timekeeping allows appropriate temporal regulation of an organism's internal metabolism to anticipate and respond to recurrent daily changes in the environment.
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