Aryl hydrocarbon receptor (AhR) impairs circadian regulation: Impact on the aging process.

Circadian clocks control the internal sleep-wake rhythmicity of 24 h which is synchronized by the solar cycle. Circadian regulation of metabolism evolved about 2.5 billion years ago, i.e., the rhythmicity has been conserved from cyanobacteria and Archaea through to mammals although the mechanisms utilized have developed with evolution. While the aryl hydrocarbon receptor (AhR) is an evolutionarily conserved defence mechanism against environmental threats, it has gained many novel functions during evolution, such as the regulation of cell cycle, proteostasis, and many immune functions. There is robust evidence that AhR signaling impairs circadian rhythmicity, e.g., by interacting with the core BMAL1/CLOCK complex and disturbing the epigenetic regulation of clock genes. The maintenance of circadian rhythms is impaired with aging, disturbing metabolism and many important functions in aged organisms. Interestingly, it is known that AhR signaling promotes an age-related tissue degeneration, e.g., it is able to inhibit autophagy, enhance cellular senescence, and disrupt extracellular matrix. These alterations are rather similar to those induced by a long-term impairment of circadian rhythms. However, it is not known whether AhR signaling enhances the aging process by impairing circadian homeostasis. I will examine the experimental evidence indicating that AhR signaling is able to promote the age-related degeneration via a disruption of circadian rhythmicity.

Salminen A 《-》

Aryl hydrocarbon receptor impairs circadian regulation in Alzheimer's disease: Potential impact on glymphatic system dysfunction.

Circadian clocks maintain diurnal rhythms of sleep-wake cycle of 24 h that regulate not only the metabolism of an organism but also many other periodical processes. There is substantial evidence that circadian regulation is impaired in Alzheimer's disease. Circadian clocks regulate many properties known to be disturbed in Alzheimer's patients, such as the integrity of the blood-brain barrier (BBB) as well as the diurnal glymphatic flow that controls waste clearance from the brain. Interestingly, an evolutionarily conserved transcription factor, that is, aryl hydrocarbon receptor (AhR), impairs the function of the core clock proteins and thus could disturb diurnal rhythmicity in the BBB. There is abundant evidence that the activation of AhR signalling inhibits the expression of the major core clock proteins, such as the brain and muscle arnt-like 1 (BMAL1), clock circadian regulator (CLOCK) and period circadian regulator 1 (PER1) in different experimental models. The expression of AhR is robustly increased in the brains of Alzheimer's patients, and protein level is enriched in astrocytes of the BBB. It seems that AhR signalling inhibits glymphatic flow since it is known that (i) activation of AhR impairs the function of the BBB, which is cooperatively interconnected with the glymphatic system in the brain, and (ii) neuroinflammation and dysbiosis of gut microbiota generate potent activators of AhR, which are able to impair glymphatic flow. I will examine current evidence indicating that activation of AhR signalling could disturb circadian functions of the BBB and impair glymphatic flow and thus be involved in the development of Alzheimer's pathology.

Salminen A 《-》

Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity.

Jaeger C ，Khazaal AQ ，Xu C ，Sun M ，Krager SL ，Tischkau SA ... -  《-》

Aryl hydrocarbon receptor affects circadian-regulated lipolysis through an E-Box-dependent mechanism.

An internal circadian clock regulates timing of systemic energy homeostasis. The central clock in the hypothalamic suprachiasmatic nucleus (SCN) directs local clocks in peripheral tissues such as liver, muscle, and adipose tissue to synchronize metabolism with food intake and rest/activity cycles. Aryl hydrocarbon receptor (AhR) interacts with the molecular circadian clockworks. Activation of AhR dampens rhythmic expression of core clock genes, which may lead to metabolic dysfunction. Given the importance of appropriately-timed adipose tissue function to regulation of energy homeostasis, this study focused on mechanisms by which AhR may influence clock-controlled adipose tissue activity. We hypothesized that AhR activation in adipose tissue would impair lipolysis by dampening adipose rhythms, leading to a decreased lipolysis rate during fasting, and subsequently, altered serum glucose concentrations. Levels of clock gene and lipolysis gene transcripts in mouse mesenchymal stem cells (BMSCs) differentiated into mature adipocytes were suppressed by the AhR agonist β-napthoflavone (BNF), in an AhR dependent manner. BNF altered rhythms of core clock gene and lipolysis gene transcripts in C57bl6/J mice. BNF reduced serum free fatty acids, glycerol and liver glycogen. Chromatin immunoprecipitation indicated that BNF increased binding of AhR to E-Box elements in clock gene and lipolysis gene promoters. These data establish a link between AhR activation and impaired lipolysis, specifically by altering adipose tissue rhythmicity. In response to the decreased available energy from impaired lipolysis, the body increases glycogenolysis, thereby degrading more glycogen to provide necessary energy.

Khazaal AQ ，Haque N ，Krager CR ，Krager SL ，Chambers C ，Wilber A ，Tischkau SA ... -  《-》

Aryl hydrocarbon receptor-deficient mice are protected from high fat diet-induced changes in metabolic rhythms.

Jaeger C ，Xu C ，Sun M ，Krager S ，Tischkau SA ... -  《-》