Lack of sleep is increasingly associated with weight gain and metabolic problems. Interfaces between the pathways that regulate circadian timing and metabolism might underlie these adverse health effects. Jill Jouret reports.
Getting a good night’s sleep is a basic, but often eluded, prescription for good health. Modern lifestyles provide opportunities for 24 h activity, and minimising sleep is often thought to be a harmless, efficient, or merely necessary means to accommodate schedules. However, feeling tired at night is more than an instruction to rest. Behaviour and physiology are intricately linked to light and dark cycles, and an internal timing mechanism has evolved to ensure that physiological processes occur at optimum times in a 24 h cycle. Maintaining the synchrony of this endogenous circadian clock seems to have wide-ranging health implications.
Although the mechanisms are not fully clear, evidence is mounting that insufficient sleep and disruption in circadian rhythms contribute to pathogenesis of metabolic disorders, cardiovascular disease, and cancer. Worldwide, metabolic syndrome is on the rise, as is the introduction of artificial light and activity into night-time hours. Epidemiological and clinical studies have shown that short-duration and poor-quality sleep predict development of type 2 diabetes and obesity, suggesting that sleep, circadian rhythms, and metabolic systems are interconnected.
In mammals, circadian rhythms are generated centrally by the suprachiasmatic nuclei in the anterior hypothalamus. Light perception by the retina synchronises these single-celled oscillators, generating rhythmic outputs that regulate sleep and wakefulness, feeding and energy expenditure, and glucose homoeostasis. This central clock also sends signals via direct innervation and humoral factors to clock components in peripheral tissues, thus maintaining the circadian timing of an array of physiological processes. Transcription—translation feedback loops implicating specific clock genes lead to a roughly 24 h cycle.
Molecular links between circadian and metabolic pathways have been identified and many hormones implicated in metabolism and energy balance exhibit circadian oscillation—eg, expression and secretion of leptin, a hormone that signals satiety, peaks at night. The complex signalling systems that govern glucose homoeostasis and metabolism of fatty acids, cholesterol, bile acids, and toxins receive inputs from the local and central circadian clocks, allowing cells to anticipate metabolic reactions in a 24 h period. In-vitro studies show that metabolic cues can be transmitted to core components of the circadian clock. Such crosstalk suggests a mechanism by which eating (and possibly sleeping) patterns could shift innate circadian timing.
A study published in March, 2013, by a group at the University of Surrey (Guildford, UK) highlighted the interconnection between sleep, circadian rhythmicity, and metabolism. Whole-blood RNA samples were taken from participants after a week of restricted nightly sleep (5·7 h) and also after a week of adequate sleep (8·5 h). Transcriptome analysis showed that 711 genes were upregulated or downregulated by insufficient sleep, including genes associated with circadian rhythms and metabolism.
Sleep restriction also reduced the total number of genes with circadian expression profiles, implying that even a week of poor sleep can disrupt the body’s intricate physiological timing.
Melatonin, a key regulator of sleep, could be an important link connecting circadian timing and insulin signalling. Melatonin production is suppressed by light, and peaks around 3—5 h after sleep onset; it regulates the sleep—wake cycle by lowering body temperature and causing drowsiness, and also inhibits insulin secretion by pancreatic β cells. A 2013 case-control studywithin the Nurses’ Health Study cohort showed that, compared with women in the highest category of melatonin secretion, women in the lowest category had about a twice the risk of developing type 2 diabetes (after controlling for demographic, lifestyle, and other risk factors). Previous studies have shown that single nucleotide polymorphisms of the melatonin receptor are also associated with an increased risk of type 2 diabetes.
More clinical research is needed to characterise this association between sleep, melatonin concentrations, and type 2 diabetes, and to elucidate, for example, whether melatonin supplementation has a role in treatment. Irregular and extended working hours are a reality for many industries, and epidemiological studies have shown lower melatonin concentrations in night-shift workers than in day-shift workers and an increasing risk of type 2 diabetes with number of years of shift work. For this substantial proportion of the workforce, more solutions are needed to prevent people from falling into economically driven health traps.
Insufficient sleep is a risk factor for weight gain and obesity, in addition to type 2 diabetes, and understanding the underlying mechanisms could help to guide novel weight-loss strategies. A study published on April 2, 2013, showed that eating behaviours, particularly night-time eating, contributed to weight gain during sleep loss. Whole-room calorimetry measured daily energy expenditure in adults undergoing 5-day cycles of inadequate (5 h) or adequate (9 h) nightly sleep. Energy expenditure was about 5% higher with insufficient sleep, but increased food intake more than compensated for this energetic cost. In the sleep-loss condition, participants ate a smaller breakfast but consumed 42% more calories as after-dinner snacks, leading to weight gain. The study investigators suggested that participants’ eating patterns during sleep loss resulted from a delayed circadian phase—ie, a later onset of melatonin secretion at night, assessed by hourly blood samples from an intravenous catheter—which might have led to a circadian drive for more food intake. Furthermore, the time between waking and melatonin offset was longer in the 5 h sleep condition; thus, participants awoke during an earlier circadian phase (while still in biological night) and might have been less hungry for breakfast. Previous studies have suggested that disrupted signalling of satiety and hunger hormones leads to the overeating associated with insufficient sleep; however, in both the 5 h and 9 h conditions, excessive food intake was accompanied by appropriate increases in the satiety hormones leptin and peptide YY and decreases in ghrelin, which stimulates hunger.
Future studies should examine how sleep deprivation leads to delays in circadian phase and how circadian timing of meals affects energy metabolism. For the millions of people whose working week necessitates a disrupted sleep schedule, a physiological drive for more food intake, the availability of high-calorie foods, and exhaustion leading to less physical activity overall could be a potent formula for weight gain.
Whether for work, play, or travel, voluntary sleep curtailment has become endemic; however, restricted sleep seems to interfere with the crosstalk between complex physiological and circadian networks that have evolved to couple our bodily functions with the Earth’s 24 h rotation. Many more issues deserve investigation, such as the differential effects on health of acute versus chronic sleep deprivation, and how light exposure mediates the effects of sleep loss. As more evidence emerges of the circadian orchestration of metabolism, perhaps the time has come for sleep to figure more prominently in treatment and public health guidelines.