The Suprachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sensitivity

Coomans, Claudia P.; Berg, Sjoerd A.A. van den; Lucassen, Eliane A.; Houben, Thijs; Pronk, Amanda; Spek, Rianne van der; Kalsbeek, Andries; Biermasz, Nienke R.; Dijk, Ko Willems van; Romijn, Johannes A.; Meijer, Johanna H.

doi:10.2337/db12-0507

Cited by 155 publications

(119 citation statements)

References 51 publications

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“…Both rodent and human studies confirm that daily rhythms of blood glucose and insulin secretion are regulated by the timing system [53][54][55], whilst lesions of the SCN or environmental circadian disruption can lead to insulin resistance and obesity [56,57]. The molecular clock is essential for glucose metabolism, as evidenced by the impairment of glucose tolerance and insulin sensitivity upon disruption of core clock gene expression [51,[58][59][60][61][62][63].…”

Section: The Timing System and Glucose Homeostasismentioning

confidence: 92%

“…Though SCN-driven neuroendocrine and autonomic outflow influence glucose homeostasis [64], peripheral clocks in the liver and pancreas also play a role in glucose management [10,[65][66][67][68][69]. We will avoid discussion of SCN-driven cues here, as their contribution has been reviewed elsewhere [10,56,64,70,71]. Instead, we will focus on clock function within the liver and pancreas as it relates to direct tissue level control of glucose homeostasis.…”

Section: The Timing System and Glucose Homeostasismentioning

confidence: 99%

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Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.

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Section: The Timing System and Glucose Homeostasismentioning

confidence: 92%

Section: The Timing System and Glucose Homeostasismentioning

confidence: 99%

Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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“…The SCN-controlled biological clock rhythm is crucial for maintaining hepatic insulin sensitivity (6). In the current study, we investigated the underlying mechanisms and found that 1) hypothalamic orexin bidirectionally regulates hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation.…”

Section: Discussionmentioning

confidence: 88%

“…The daily rhythm of HGP is regulated by the autonomic nervous system under SCN control, leading to generation of a daily rhythm in basal blood glucose levels independently of the feeding rhythm (5). The central clock is also crucial for preventing metabolic abnormalities in the liver, since lesions of the SCN caused severe hepatic insulin resistance in mice (6); however, the underlying mechanisms remain uncertain. It is of note that nutrient excess causes endoplasmic reticulum (ER) stress in hepatocytes, a main cause of hepatic insulin resistance, and the cells need "resting time" to recover from the ER stress (7,8).…”

mentioning

confidence: 99%

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

et al. 2014

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Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wildtype mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.Maintaining glucose and energy homeostasis throughout the day is essential for survival. Therefore, different metabolic functions are timely activated according to the circadian rhythm. Recently, it has also become clear that fine tuning of daily metabolic rhythms is crucial for preventing metabolic abnormalities. For instance, chronic disruption of circadian rhythm in humans, as seen in shift workers, increases the risk of obesity and type 2 diabetes (1,2), and circadian rhythms of glucose regulation are impaired in diabetic animals and patients with diabetes (3).Circadian rhythms of peripheral tissues, including liver, are entrained to the central biological clock located in the suprachiasmatic nuclei (SCN) via autonomic and hormonal pathways (4). The liver plays a pivotal role in maintaining optimal glucose levels via hepatic glucose production (HGP) and glucose uptake. The daily rhythm of HGP is regulated by the autonomic nervous system under SCN control, leading to generation of a daily rhythm in basal blood glucose levels independently of the feeding rhythm (5). The central clock is also crucial for preventing metabolic abnormalities

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“…Peripheral circadian oscillators have been demonstrated in both white and brown adipose tissues that play a prominent role in energy conservation and adaptive metabolic responses [68][69][70]. Additionally, normal satiety hormone levels, such as leptin [71], ghrelin [72], insulin [73], and glucagon [74], tend to exhibit circadian oscillation. Finally, functional connections between core clock genes and metabolic processes are increasingly being characterized using mutant mice.…”

Section: Circadian Clock and Metabolismmentioning

confidence: 99%

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

Zubidat

Haim

2017

Journal of Basic and Clinical Physiology and Pharmacology

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Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.

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The Suprachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sensitivity

Cited by 155 publications

References 51 publications

Chronomedicine and type 2 diabetes: shining some light on melatonin

Chronomedicine and type 2 diabetes: shining some light on melatonin

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

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