The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

a sleeping ladya sleeping ladyAbstract: The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity.

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Alex’s Notes: Ideally, humans would sleep for about one-third of their lifetime. The regulation of our wake-sleep patterns are owed to our circadian rhythms, an autonomous mechanism that interacts with gene expression in every corner of the body. The major site of circadian rhythm regulation, in turn, is the suprachiasmatic nucleus (SCN) located within the hypothalamus snuggly above the optic chasm (eyes). Overall, sleep, eating, and general behavior interact with the environment to influence our circadian rhythm and subsequently affect hormonal and metabolic processes within the body.

As an example, we can look to the natural rhythms of several hormones. Growth hormone levels peak immediately after sleep onset, and concentrations appear to be greater during slow-wave sleep (SWS) compared with stages 1 & 2 REM sleep. This is further exemplified in post-traumatic stress disorder patients characterized by constant sleep disturbances who demonstrated lower nighttime growth hormone levels compared to healthy controls. Contrast to growth hormone, cortisol levels increase rapidly from the middle of the night onward, peaking about 30 minutes after waking.

The most well-known circadian hormone is melatonin, which is increased during the night and suppressed with daylight. It has been known for a while that exogenous melatonin can improve sleep quality without affecting the proportions of SWS or REM sleep. Thyroid-stimulating hormone (TSH) appears to peak in the middle of the night and reach a nadir in the afternoon, whereas T3 and T4 are not associated with circadian rhythms. Finally, two master hormones for the promotion and reduction of food intake are ghrelin and leptin, respectively, both of which have been shown to increase SWS while reducing REM sleep.

Regarding metabolic processes, the best examples come from looking at carbohydrate and lipid metabolism. Indeed, a recent systemic review concluded that hepatic glucose output is intimately tied to circadian regulation, as demonstrated by numerous gene-knockout experiments in rodents. In fact, the authors of the review suggest that the hyperglycemia observed in the knock-out animals may be due primarily to a reduced insulin release and not so much to insulin resistance. In other words, the problems may lie in the pancreas and its circadian controls rather than in the peripheral tissues. Circadian disorganization also promotes hyperlipidemia and fat storage in white adipocytes and the liver. Indeed, several genes involved in lipid metabolism demonstrate circadian rhythms.

And it all starts with sleep

The time our days start and end is arbitrary, as emphasized by the (in my opinion) stupid daylights saving time changes that occur twice per year. The only true determinant of a day’s start and end is wake and sleep, respectively. Thanks to the influence of sunlight and darkness on our biological clocks, we are deeply in tune with the universe for this. Thus, it is worth looking at how sleep duration plays a role in our health, especially considering how pervasive modern life and technology is.

Sleep duration may be associated with becoming obese, and a sleep debt greatly increases this risk. Notably, one longitudinal study examined the relationship between sleep duration and long-term changes in visceral fat (VAT) and found that baseline short (≤6 h/day) and long (≥9 h/day) sleepers gained significantly more VAT than those reporting sleeping 7-8 hours a night. However, changing from being a short to an average sleeper was protective against VAT accumulation.

Sleep duration is also a risk factor for type-2 diabetes. As mentioned previously, circadian rhythms play a central role in carbohydrate metabolism. Compared to sleeping nine hours per night, restricting the sleep duration of young, healthy males to four hours per night for one week considerably lowers glucose tolerance and thyrotropin concentrations while increasing cortisol and sympathetic activity. A growing body of evidence also suggests that sleep deprivation increases insulin resistance, likely through interference with cell-signaling.

Between increasing fat accumulation and impairing glucose metabolism, the fact that sleep deprivation increases ghrelin, hunger, and appetite, especially for carbohydrate-rich foods, may underlie the associations with obesity and type-2 diabetes. Not surprisingly, this hunger and appetite greatly increases caloric intake for the day, primarily through snacks at night. Interestingly, MRI scanning of the brain during sleep restriction shows reduced activity of the frontal cortex and insular cortex combined with amplification of the amygdala, indicating less rational and more emotion decision making. These changes are associated with a significant increase in the desire for weight-gain promoting high-calorie foods following sleep deprivation, the extent of which is predicted by the subjective severity of sleep loss across participants. Even a single night of complete sleep deprivation (i.e. an all-nighter) reduces resting and postprandial energy expenditure.

A note on shift work

Beyond sleep itself, when we are awake also plays a role in health. The best possible example is shift workers who are characterized by significantly greater postprandial glucose, insulin, and triglyceride responses which collectively increase the risk for metabolic syndrome, obesity, and type-2 diabetes. Whether night workers’ greater body fat mass, reduced insulin sensitivity, increased triglycerides, and increased post-meal ghrelin response are the cause or result of these associations has yet to be determined.

That said, evidence strongly supports the notion that circadian disorganization causes problems. One fascinating study purposely employed an 11-day forced desynchronization protocol on ten healthy adult men and women. All subjects ate and slept at all phases of the circadian cycle – achieved by scheduling a recurring 28-hour “day” within the laboratory under dim light conditions to minimize any influence of light on the circadian system. During each “day” the subjects consumed the same 4 isocaloric meals (25% fat, 50% carbohydrate, and 25% protein) at 1, 5, 11.5, and 15.5 hours post-awakening. It was found that this short-term circadian misalignment, similar to that which occurs acutely with jet lag and chronically with shift work, results in systematic increases in postprandial glucose, insulin, and mean arterial pressure, systematic decreases in leptin and sleep efficiency, and the complete inversion of the cortisol profile across the behavioral cycle.

Since the abnormally high cortisol at the beginning of sleep could contribute to insulin resistance and hyperglycemia, and the reduced leptin stimulates appetite and decreases energy expenditure, the authors of this above study suggest these combined effects to be at least one mechanism behind the increased risk for obesity hypertension, and diabetes in shift workers.

Bottom line

Get some sleep… seriously (also don’t work night shift if you can help it).


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