Role of Aryl Hydrocarbon Receptor in Circadian Clock Disruption and Metabolic Dysfunction

Abstract

The prevalence of metabolic syndrome, a clustering of three or more risk factors that include abdominal obesity, increased blood pressure, and high levels of glucose, triglycerides, and high-density lipoproteins, has reached dangerous and costly levels worldwide. Increases in morbidity and mortality result from a combination of factors that promote altered glucose metabolism, insulin resistance, and metabolic dysfunction. Although diet and exercise are commonly touted as important determinants in the development of metabolic dysfunction, other environmental factors, including circadian clock disruption and activation of the aryl hydrocarbon receptor (AhR) by dietary or other environmental sources, must also be considered. AhR binds a range of ligands, which prompts protein–protein interactions with other Per-Arnt-Sim (PAS)-domain-containing proteins and subsequent transcriptional activity. This review focuses on the reciprocal crosstalk between the activated AhR and the molecular circadian clock. AhR exhibits a rhythmic expression and time-dependent sensitivity to activation by AhR agonists. Conversely, AhR activation influences the amplitude and phase of expression of circadian clock genes, hormones, and the behavioral responses of the clock system to changes in environmental illumination. Both the clock and AhR status and activation play significant and underappreciated roles in metabolic homeostasis. This review highlights the state of knowledge regarding how AhR may act together with the circadian clock to influence energy metabolism. Understanding the variety of AhR-dependent mechanisms, including its interactions with the circadian timing system that promote metabolic dysfunction, reveals new targets of interest for maintenance of healthy metabolism.

Carbamate Insecticides Target Human Melatonin Receptors

“…61 However, to date the interactions of environmental chemicals with human melatonin receptors have not been reported in the literature. Interactions of carbamates with MT 1 and MT 2 receptors expressed in the brain (e.g., SCN) and peripheral tissues (e.g., pancreatic β -cells) responding to endogenous melatonin may alter melatonin receptor sensitivity and signaling leading to disruptions in the rhythmic and homeostatic balance of key regulatory processes 1,18,58–60 and metabolic functions.…”

Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

“…AHR-signaling is now known to participate in: cell migration (Mulero-Navarro and Fernandez-Salguero, 2016), epithelial cell development (Ikuta et al , 2009), cytoskeletal/adhesion regulation (Zhang et al , 2016), circadian rhythmicity (Anderson et al , 2013), barrier organ physiology (Esser and Rannug, 2015), cardiovascular and respiratory physiology (Sauzeau et al , 2011b), kidney development (Nanez et al , 2011), inner ear cochlear development in the neonate (Safe and Luebke, 2016), bone formation (Herlin et al , 2013) and osteoclastogenesis (Iqbal et al , 2013; Izawa et al , 2016), GI tract (Hubbard et al , 2015; Schiering et al , 2016), intestinal immunity (Qiu and Zhou, 2013), innate immunity (Cella and Colonna, 2015), hematopoiesis (Lindsey and Papoutsakis, 2012; Fracchiolla et al , 2016), transgenerational inheritance (Baker et al , 2014), reproductive organ development (Mulero-Navarro and Fernandez-Salguero, 2016), regulation of female reproduction (Hernandez-Ochoa et al , 2009), prostate gland development (Schneider et al , 2014), hyperlipidemia, atherogenesis, and hypertension (Xiao et al , 2014), thyroid-associated eye disease (Woeller et al , 2016), eye and ciliary body function (Shichi and Nebert, 1982; Volotinen et al , 2009), hepatic steatosis (Mellor et al , 2016), pancreatic beta-cell regulation (Sabatini and Lynn, 2015), glucose and lipid metabolism (Gooley, 2016), circadian clock and metabolic syndrome disruption (Jaeger and Tischkau, 2016), DNA damage control (Wells et al , 2010), tumor prevention by regulating gut immunity and growth suppression in tumor cells (Ikuta et al , 2016), and protection against oxidative stress (Wölfle et al , 2014). …”

Hypoxic Upregulation of ARNT (HIF-1β): A Cell-Specific Attribute with Clinical Implications

“…Within the nucleus activated AhR can dimerise with BMAL1 thus disrupting the autoregulatory loop of BMAL1/Clock genes. Therefore, AhR activation leads to a suppression of circadian rhythms, whereas AhR inhibition strengthens rhythm amplitude [25]. Interestingly, there is evidence that both AhR and ARNT are expressed in an oscillatory pattern in vivo [29].…”

“…They belong to the group of Per-ARNT-Sim (PAS) transcription factors which are characterised by the presence of a PAS domain (composed of PAS-A and PAS-B subdomains) required for protein-protein interactions. Therefore, all family members are able to form homo-and heterodimers among the group [9,25].…”