Circadian Slocks And Metabolism
In mammals the suprachiasmatic nucleus of the hypothalamus is the master circadian clock for the entire body. The clock controls the sleep/wake cycle because it is synchronized with solar time. However, the clock has many other features such as the regulation of physical and chemical functions of the body. The circadian system orchestrates metabolism in daily 24-hour cycles. Such rhythms organize metabolism by temporally separating opposing metabolic processes and by anticipating recurring feeding-fasting cycles to increase metabolic efficiency. Circadian clocks are pivotal to organisms because they are independent and they function consistently around the clock. The SCN circadian clock is synchronized to environmental light cues captured by rods, cones and melanopsin-containing retinal ganglion cells (mRGCs), cues are delivered directly through the retinohypothalamic tract to the SCN. The SCN takes the information from the retina, interprets it and passes it on to the pineal gland which is located in the epithalamus. Melatonin is a hormone secreted in the pineal gland and is used to regulate wakefulness. Insufficient amounts of sleep can misgauge the circadian rhythm leading to a lot of complications in health, including sleep disorders, obesity, bi polar disease and many other diseases that can be fatal. Prior to the discovery of molecular clock genes, a prevailing model held that circadian rhythms represent a unique property of pacemaker neurons. However, many different experiments performed in the 1990s have established the presence of cell-autonomous circadian gene rhythmic expression in cultured fibroblasts, demonstrating the uniqueness of circadian transcriptional oscillators throughout all cells.
Circadian clocks are physical, mental, and behavioral changes that follow a specific daily cycle (1). Circadian coming from the Latin origins “circa”, which means “around”, referring to the cycle or the rhythm of the circadian clock. Humans perform many activities daily and the circadian clock helps regulate the human body. Circadian clocks are biochemical oscillators that are synchronized with solar time. Circadian rhythms are produced by the biological clock and by which they are regulated. Biological clocks are found in almost every tissue and organ throughout the human body, including organs that are essential for cardio-metabolic functions, such as the liver, the pancreas, the muscles, and one of the most important organs that keeps you alive and pumping blood, the heart. A fundamental feature of all circadian rhythms is their consistency in the absence of any environmental cues and their ability to be self-sustainable. This ability of clocks to “free-run” in constant conditions at periods slightly different than 24 hours, but yet synchronized, allows organisms to anticipate and prepare for cyclic changes in the environment (2).
Circadian rhythms are very important in the human body because they do not require an on/off switch rather they function on their own through signals and neurons and regulate the body accordingly. There are four main components in the circadian clock, CLOCK, BMAL1, CYCLE, and NPAS2. These 4 components work together to regulate the circadian clock. When one of these components is used too much or too little, miscommunication can occur leading to dysfunction of the circadian rhythm, eventually causing diseases and disorders. The two proteins include involved include CLOCK and BMAL1 which are both positive regulators. The genes that work alongside the protein are periods (Per1, Per2, and Per3), two Cryptochromes (Cry1 and Cry2). These genes make the proteins that are considered the negative part of the feedback system.
Negative effects of metabolism are shown from miscommunication of the circadian clock and irregularities in rhythm. Circadian clocks play a major role in metabolism. Metabolism is a process by which our cells change the food we eat into energy our bodies need to participate in many daily activities such as eating, breathing, thinking and other activities. The three main purposes of metabolism are the conversion of food to energy to function cellular processes, the conversion of food to fuel to building blocks for proteins, lipids, nucleic acids, some carbohydrates and the elimination of nitrogen waste (4). Metabolism is regulated by the thyroid gland. The thyroid gland is a large ductless gland in the neck that regulates growth and development through the rate of metabolism by secreting hormones. The focus of this paper is the circadian clock and the role it plays in metabolism. Mentioned in this paper as well will also be discussing the complications that may rise due to irregularities and dysfunctions in the circadian rhythm and metabolism.
Circadian clocks help organisms anticipate and prepare for environmental changes. They help organisms take better advantage of the resources of their environment such as light and food. Rhythm is important in regulating and coordinating internal processes as well as coordinating it with environmental changes. Circadian and metabolic processes interact at both the neuroanatomic and neuroendocrine levels to regulate overall metabolic homeostasis (14). Circadian clocks are synchronized with solar time. Due to the synchronized feature of the circadian rhythm with the light of day and darkness of night, different genes are activated or deactivated. Once light signals are received they are sent to the suprachiasmatic nucleus (SCN).
A master clock in the brain coordinates all the biological clocks in a living organism, keeping the clocks in sync. In vertebrate animals, including humans, the master clock is a group of about 20,000 nerve cells (neurons) that form a structure called the suprachiasmatic nucleus, or SCN. The SCN is located in a part of the brain called the hypothalamus and receives direct input from the eyes (1). The hypothalamus is a portion of the brain that mainly functions in linking the nervous system to the endocrine system via the pituitary gland. Most tissues and cells are found to display circadian patterns of gene expression when isolated from the SCN. Therefore, the SCN serves to synchronize the individual cells of the body to a uniform internal time (2).
In mammals the suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock for the entire body. The suprachiasmatic nucleus (SCN) is located in a small region of the brain The hypothalamus, sitting directly above the optic chiasm. The suprachiasmatic nuclei (SCN) is important in controlling and regulating daily physiological and behavioral circadian rhythms. The SCN circadian clock is synchronized to environmental light cues captured by rods, cones and melanopsin-containing retinal ganglion cells (mRGCs), cues are delivered directly through the retinohypothalamic tract to the SCN. The SCN takes the information from the retina, interprets it and passes it on to the pineal gland, which is located in the epithalamus. The pineal gland secretes the hormone melatonin, which helps with regulating sleep and wakefulness. The secretion of melatonin is greater at night than during the day because melatonin makes you sleepy. when the organism is asleep melatonin is produced in greater amounts so that the organism sleeps through the night and stays awake during the day.
The SCN is a bilaterally organized structure that contains approximately 20,000 neurons. Each neuron generates a circadian rhythm in electrical activity, with high ensemble neuronal activity in the middle of the instinctive day (2). Molecular and cytosolic clocks interact to produce a circadian rhythm in cellular physiology and neuronal excitability (11). The circadian clock is regulated by the epithalamus. The epithalamus functions mainly in connecting the limbic system to other parts of the brain. Other functions of the epithalamaus involved with the circadian clock include the secretion of melatonin and secretion of hormones from the pituitary gland by the pineal gland as well as many other functions. This epithalamic complex is anatomically divided into medial (MHb) and lateral (LHb) regions and it is implicated in learning, memory, attention, sleep/wake cycles and anxiety (13).
There are two main segments to the circadian clock, the master clock which generates a roughly 24hour rhythm, and the peripheral clock, that takes environmental changes and corrects the phases of circadian oscillation. Clock genes are driven by a sequence of molecular transcriptional or translational feedback loops (TTFL) which expresses itself. Oscillating proteins are the translational feedback loops (TTFLs) that control the timekeeping mechanisms, while the central pacemaker neurons set a specific time relative to the environment. These neurons express different functions or do not show expression when stimulated by various stimuli.
An example of a circadian rhythm is sleep-wake cycle which is sleeping at night and being awake during the day. The circadian clock manages rhythmicity within an organism far beyond the sleep activity cycle. In humans and most mammals there are 24 hour rhythms in body temperature, blood pressure, circulating hormones, metabolism, retinal electroretinogram (ERG) responses, as well as a host of other physiological parameters (2). Although, circadian clocks govern so many different activities in the body, they also regulate in particular metabolism.
Circadian clocks role in metabolism
Many aspects of normal biological function are governed by circadian rhythms, including metabolism, behaviors, and sleep-wake cycles. Certain pathological processes as well are also affected by circadian rhythms. For example, through many studies conducted by researchers, we know that seizure occurrence can be influenced by the sleep-wake cycle (15). Circadian clocks control a wide variety of physiological events, including metabolism, in all organisms. Studies show that connections between the circadian clock and the cellular metabolism have been identified to be regulated by chromatin remodeling. Suggesting that abnormal metabolism in cancer could also be a consequence of a disrupted circadian clock rhythm. Therefore, a comprehensive understanding of the molecular links that connect the circadian clock to the cell cycle and metabolism could provide therapeutic benefit against certain human neoplasia (6).
Rooted in our modern life-style is the flexibility to eat, sleep, socialize, and exercise around the clock, yet these allowances correlate with rising metabolic disorders and obesity (7). Metabolic homeostasis, which refers to a stable internal temperature and a stable environment which will allow metabolism to function to its maximum ability, relies heavily on accurate circadian rhythms within individual cells and tissues of the body. The neuroendocrine system is a mechanism that the hypothalamus uses to maintain homeostasis, regulate metabolism, reproduction, eating and drinking behavior, energy utilization, osmolarity and blood pressure. The regulation of metabolism, is carried out by hypothalamic interconnections to other glands. Clock-Controlled Genes (CCGs) control the molecular processes and metabolism in the circadian clock (10).
The circadian system orchestrates metabolism in a daily 24-hour cycles. Such rhythms organize metabolism by temporally separating opposing metabolic processes and by anticipating recurring feeding or fasting cycles to increase metabolic efficiency (4). At the center of these rhythms resides the circadian clock machinery, an incredibly well-coordinated transcription/translation feedback system that incorporates a changing landscape of mRNA expression, protein stability, chromatin state, and metabolite production, utilization, and turnover to keep correct time (7).
Environmental effects on circadian clocks
Circadian clocks depend on environmental cues, therefor they require a stable environment with rhythmic homeostasis and very little to no changes that might disorganize the rhythm. Knowing that circadian rhythms depends on environmental cues, any shifts or changes can alter the circadian rhythm. Perturbations in the circadian rhythm can develop under a variety of conditions, including ageing, neurodegenerative diseases and metabolic disorders. In order to effectively treat these diseases, it is important to elucidate the causal relationships behind these associations. Under the influence of environmental conditions, synchronization can either increase or decrease, leading to a more compressed or decompressed waveform of the neuronal population (11). Any irregularities in circadian rhythms can eventually lead to fatal diseases and disorders.
Disorders due to irregular circadian rhythms
Circadian rhythms can have an influence on many different body activities such as sleep-wake cycles, hormone release, eating habits, digestion, body temperature, and other important bodily functions (14). Biological clocks that run fast or slow can result in disrupted or abnormal circadian rhythms. Irregular rhythms and sleep deficiencies have been linked to various diseases and disorders such as chronic health conditions, including sleep disorders, obesity, diabetes, depression, bipolar disorder, heart disease and strokes (1).
Sleep is a very important biological process, that if neglected can cause rhythm divergence. Sleep plays many important roles such as healing and repair for the heart and blood vessels, as well as your overall physical health. Working a night shift plays an important role in throwing the circadian rhythm off its course. Epidemiological studies show that disruption of this internal synchronization caused by short sleep and shift work is associated with adverse health outcomes through mechanisms that remain to be elucidated (10). As previously mentioned, peripheral clocks regulate glucose and lipid homeostasis and mutations in BMAL1 and CLOCK which lead to metabolic disorders. An altered and inconsistent feeding schedule can and most likely will cause the peripheral oscillators to be separated from the suprachiasmatic nucleus (11). People who work night shifts have an increased irregularity in circadian rhythms, because they do not have a set sleeping schedule. Dysfunctions in circadian clocks and irregular rhythms lead to improper regulation of the human body causing many diseases and disorders in the human body.
Circadian rhythm disturbances and diseases can also be caused by not following a specific eating schedule. Peripheral clocks separate from the central clock which leads to inconsistency in the food and light cues, causing the central clock to coincide primarily to food cues. Many complications in the human body rise due inconsistency in the eating habits and not having a set schedule for regular eating times. Insulin secretion uses clock-controlled protein equipment to permit insulin exocytosis to occur and let nutrients be ingested. Insulin is a hormone secreted in the pancreas and is used to maintain blood sugar levels and keep them in equilibrium. Stimulations reveal a shift in the clock which create an incomplete inversion of exocytosis. This causes a lower insulin secretion and an increase in glucose levels, producing metabolic diseases (12).
Irregularities also cause blood pressure. Blood pressure decreases by almost 10% during the night which causes the circadian proteins to “dip” meaning decrease. People that do not have dipping, during the night are more prone to heart attacks due to an increase in cardiovascular activity. People with type 2 diabetes, hypertension or kidney disease do not experience dipping. People who remain active during the night or are upright and standing have blood pressure dips but do not excrete sodium. Sodium is required for circadian balance. Humans with normal sleeping schedules and also lie down and sleep at night have normal sodium secretion and blood pressure dipping. Heart rates decrease at night which have positive effect on a normal and steady heart beat during daily activities.
The circadian clock is the master clock which plays pivotal roles in proper regulation of the human body. Humans put their bodies through a lot daily and circadian clocks do a lot of work that most of us do not know about or even notice happening. The circadian clock helps organism anticipate and prepare for environmental changes. It responds to stimuli, such as light and dark cues due to its synchronization with solar time and responds to cues accordingly. The role of circadian clocks in metabolism is very important and can affect the human body in many different ways. Changes in metabolism have shown effects on the body such as affecting the sleep-wake cycle as well as other daily functions. Insomnia, obesity, high blood pressure, sleep disorders, diabetes, depression, bipolar disorder, are just some of the effects of the dysfunction of the circadian clock.