Does Circadian Rhythm Play A Role In Metabolic Disease?

In accord with the daily rising and setting of the sun, essentially all our behaviors and physiological activities including metabolic processes show rhythmic coordination with a period of approximately 24 hours.

The main healthcare problem in many societies today stems from obesity and the number of obese individuals, including childhood obesity is increasing rapidly.

Research indicates that metabolic stress disturbs physiological clock fluctuation and genes associated with circadian rhythm. Physiological circadian fluctuation is impaired in modern societies due to shift work, nocturnal social activities, jet lag and other factors.

Peripheral clocks

Recent research has focused on the clocks (oscillators) in peripheral tissues such as the adipose tissue, liver and pancreas, and have examined the pivotal role of peripheral clocks in maintenance of tissue homeostasis and systemic metabolism.

The major roles of these peripheral clocks are orchestration of food intake and metabolic processes.

There’s evidence that the levels of many metabolites show fluctuation in the tissues and plasma, and there is accruing evidence indicating distress of peripheral clock expression has a pivotal role in the development of systemic metabolic dysfunction. Below, we will look at how circadian rhythm impacts some of these peripheral tissues.

Adipose (fat) tissue

White adipose tissue was initially thought to be mainly involved in energy storage, but it is currently widely accepted to have an endocrine function and secretes a variety of factors referred to as adipokines.

Metabolic stress associated with obesity leads to the development of sterile inflammation in white adipose tissue, which promotes a shift toward production of pro-inflammatory adipokines that contributes to the development of systemic metabolic dysfunction and diabetes⁽¹⁾.

Disruption of fat cells clock function results in temporal changes in plasma concentration of polyunsaturated fatty acids, leading to corresponding changes in the expression of neurotransmitters responsible for appetite regulation.

Development of chronic inflammation in white adipose tissue has a pathological role in the progression of systemic metabolic dysfunction. Clock genes are central to regulating the responses of immune cells and play a central role in the maintenance of adipose tissue homeostasis.

Liver

The liver plays a major role in the maintenance of systemic metabolism, as it is involved in glycogen storage, protein synthesis, hormone production and detoxification. Metabolic stress is involved in the development of nonalcoholic fatty liver disease and this promotes pathologic changes related to cardiometabolic disorders⁽²⁾.

Research indicates that suppression of liver clock genes can suppress the genes involved in gluconeogenesis (i.e. generation of glucose from certain non-carbohydrate carbon substrates) and reduce liver glucose production in association with improvement of glucose tolerance.

Pancreas

The pancreas is an essential organ that produces digestive enzymes and hormones, such as insulin and glucagon. These substances aid in the breakdown of food and help regulate blood sugar levels, maintaining overall metabolic balance.

Patients with type 2 diabetes develop pancreatic β-cell dysfunction and reduced insulin secretion, which sometimes precede the diagnosis of diabetes. Islet cells within the pancreas have an autonomous circadian rhythm and insulin is released from the pancreatic islets in a circadian manner⁽³⁾. Furthermore, disruption of circadian rhythms and dietary obesity act together to promote β-cell ⁽⁴⁾.

Findings from research suggest that clock genes have a critical role in maintenance of both pancreatic and systemic metabolic homeostasis.

Blood vessels

Although dietary obesity has a marked effect on clock genes in the visceral fat, liver and pancreas, clock gene cycling is well preserved in the aorta⁽⁵⁾.

This indicates that blood vessels may be more resistant to disruption of clock function than some other organs/tissues, and that longer exposure to stress may be required to affect the vessels.

Considering the pathological role of endothelial cell dysfunction affecting key metabolic organs in the development of systemic metabolic disorders, it is highly possible that disruption of the circadian clock in vascular endothelial cells promotes systemic metabolic dysfunction⁽⁶⁾.

Skeletal muscle

Skeletal muscle is considered likely to become a therapeutic target in the fight against obesity⁽⁷⁾.

Promoting muscle growth decreases body weight due to reduction of visceral fat mass and atrophy of white fat cells. There is limited evidence about the role of skeletal muscle clock genes in the maintenance of systemic metabolic homeostasis.

We do know that inactivating a gene associated with the circadian clock leads to weight gain and a reduction in Glut4 expression in skeletal muscle associated with impairment of insulin-induced glucose uptake by muscle⁽⁸⁾.

Microbiota

The microbial gut flora influence a broad range of physiological processes including metabolism and are important as a regulator of obesity and systemic metabolic disorders. In both mice and humans, the intestinal flora exhibit diurnal oscillation that is influenced by feeding rhythms.

Removal of the host molecular clock or induction of jet lag impairs feeding rhythmicity and leads to aberrant diurnal fluctuation of the gut flora with dysbiosis, which contributes to developing glucose intolerance and obesity⁽⁹⁾.

Sleep disorders, circadian rhythm and metabolic syndrome

It is well accepted that diurnal variation of physiological rhythms is important for health and disruption of the regular circadian rhythm by working night shifts or continuously rotating shifts increases the risk of developing obesity and diabetes⁽¹⁰⁾.

Research indicates a link between sleep disturbance, impaired circadian rhythms, and metabolic disorders. A misaligned circadian rhythm produces post-eating glucose responses in the prediabetic range and promotes systemic insulin resistance⁽¹¹⁾.

Exposure to dim light at night disrupts circadian rhythms, promoting weight gain and inflammation⁽¹²⁾.

In addition, sleep duration is linked to metabolic homeostasis and the risk of diabetes. Obstructive sleep apnea develops with obesity, which induces fragmentation of sleep and systemic hypoxia, and is well known to have a role in the progression of obesity and systemic insulin resistance⁽¹³⁾.

The evidence to date indicates that circadian dyssynchrony promotes misalignment among the functions of various organs and has a pathological role in the development of systemic metabolic dysfunction. Considering that metabolic dysfunction itself promotes circadian dyssynchrony, a vicious cycle exists between obesity and clock dysfunction.

Figure: In the normal state, circadian rhythms generated by the central and peripheral clocks coordinate metabolic processes to maintain health. Metabolic stress or circadian misalignment due to nocturnal activities or jet lag leads to clock dysfunction that promotes systemic metabolic dysfunction. Adapted from⁽¹⁴⁾

Summary

There is increasing evidence of a tight connection between metabolism and circadian rhythms, and it has been shown that metabolic stress promotes disturbance of clock-related genes in several key organs.

Evidence suggests the existence of a negative feedback loop between metabolic stress and clock dysfunction.

Synchronization of behavior with metabolism by the body clock is crucial for maintenance of systemic metabolic homeostasis, but is often disrupted in modern society. Re-synchronization of circadian rhythms may be essential to combat metabolic diseases such as obesity and diabetes.

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