• Interview The scientist who watches over your dream: "Abolishing the time change would be the best thing for health"

A study concludes that women who work shifts would be less vulnerable than men to the risk of metabolic disorders induced by disruptions of the circadian cycle that lead to changes in working hours. Its authors suggest that this female resistance to circadian misalignment could be historically linked to a biological need for parenting.

The observational study of 90,000 UK workers has been completed by searching mice for the mechanisms underlying the adverse health effects of shift work. It has been observed, among other results, that male mice exposed to circadian stress have biological changes in the liver and gut microbiome that do not appear in females. Among other findings, the article addresses a novel point of view to explain gender differences and the possibility of sexual dimorphism (physiognomic variations between males and females of the same species) in resistance to circadian misalignment.

The new data, published today in the journal Science Transnational Medicine, comes from work carried out by several departments at the University of Pennsylvania (Philadelphia), led by Seán Anderson, a researcher at the Institute for Translational and Therapeutic Medicine and professor at the Perelman School of Medicine. The authors believe that these findings could "have social implications that influence the future redesign of shift work, including how to deal with transmeridian travel."

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These are the risks of sleeping too little and poorly

  • Writing: CRISTINA G. LUCIO Madrid

These are the risks of sleeping too little and poorly

It is known that circadian rhythm, known above all as the body's internal clock that regulates sleep schedules, also governs metabolic processes such as insulin sensitivity and lipid metabolism. It has also been seen that night shift workers, particularly men, as well as other people with altered circadian rhythms, would be at increased risk of metabolic diseases such as diabetes. To find out why this happens, researchers have analyzed in the UK Biobank the records of 51,990 women and 40,335 men with a history of shift work, first proving that both sexes had a higher risk of metabolic syndrome than workers in fixed hours.

The researchers then compared the microbiomes, metabolic profiles and behavioral patterns of male and female mice that had followed a high-fat diet, finding that they did not affect females exposed to abnormal day and night cycles much. However, they did record changes in the males' gut microbiome, liver metabolism and blood pressure, differences that would disappear when the scientists suppressed the gut microbiomes of both groups with antibiotic treatment.

The Harms of Circadian Misalignment

So far, several longitudinal studies have been associating shift work with cardiometabolic disorders, but without establishing causes or clarifying the mechanisms of the disease. This research group has developed a mouse model based on this type of alternating schedules to study circadian misalignment in both sexes, a phenomenon that occurs when food and sleep oppose the natural inclination of the light/dark cycle. This internal imbalance due to alteration of homeostasis appears in several metabolic diseases.

Behavioral and transcriptional rhythmicity was conserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact observed in males, even on a high-fat diet. Tissue-level changes were accompanied by dysbiosis of the gut microbiome only in male mice.

In the UK Biobank, women showed a stronger circadian rhythm and a lower incidence of metabolic syndrome than men. "We have shown that female mice are more resistant than males to chronic circadian misalignment and that these differences are conserved in humans," Anderson said.

The authors explain that circadian rhythms are endogenous oscillations that permeate nearly every aspect of our physiology, from gene transcription to behavior. These rhythms are directed by the suprachiasmatic nucleus in the hypothalamus and organized through a hierarchical network of molecular clocks. They are known to compartmentalize many homeostatic functions, such as our sleep-wake cycle, so that they occur during the optimal time of day, but their sustained disruption can worsen health.

Endogenous oscillations are also evident in more subtle functions, such as insulin sensitivity, lipid metabolism and renal filtration, there are even genetic and environmental disturbances associated with a noticeable loss of circadian rhythms, which can lead to poor health, although it is not well understood what mechanisms trigger the risks.

Other studies suggest that genetic alteration of the molecular clock produces more severe cardiometabolic dysfunction in male mice than in females and that male mice also gain much more weight after 12 weeks of biweekly phase changes than female mice, regardless of having undergone oophorectomy or estrogen replacement.

Some recent meta-analyses collected data on increased risk of developing hypertension in men who work shifts and it is also closely associated with the occurrence of diabetes and metabolic syndrome above women who do the same shifts. However, another meta-analysis provides contradictory data, with a greater impact on women who work shifts.

Protection beyond estrogen

The most important results can be summarized in that after the disturbance of the circadian rhythm the female mice achieved a faster resynchronization than the males; whereas chronic circadian misalignment overrides transcriptomic rhythm only in male mice, and changes the gut microbiome of male mice, but not that of females; that the cardiometabolic impact of misalignment differs between the sexes and that ovariectomized mice still retained oscillations in the central circadian clock machinery after misalignment.

The authors insist that they have observed a sexual dimorphism that indicates that there are other factors beyond estrogen signaling in adulthood. Other studies had previously shown that estrogens affect the circadian response to light, and mice that had their ovaries removed showed an intermediate phenotypic response, compared to male mice after circadian cycle misalignment.

This intermediate phenotype indicates that, although important, estrogen signaling in adulthood is not the only factor that confers protection against misalignment in female mice. "One caveat to this approach is that oophorectomy completely removes estrogen signaling from the entire organism, making the role of estrogen in circadian rhythm confusing with its known protective effect in cardiometabolic disease," Anderson said.

On the other hand, circadian rhythm disruption was associated with a spectrum of diseases and aging phenotypes, suggesting that a stronger circadian rhythm in women may be relevant beyond the context of shift work and misalignment. "These analyses integrate data on the sexually dimorphic impact of circadian misalignment in multiple domains and in both mice and humans," the authors stress, acknowledging limitations of the study such as not having explored transcriptional oscillations or feeding rhythms at the individual level of mice; or in the human study, they did not investigate whether the type of shift (rotating, permanent etc...) affected the risk of cardiometabolic disease.

"However, we have shown that substantial sexual dimorphism is not only in basal circadian rhythms, but also in the response to chronic circadian misalignment. We previously suggested that resilience to sleep disruption and circadian misalignment may be rooted in a biological need, reflecting the historically dominant role women have played in raising children."

That sexual dimorphism. covering all aspects the researchers measured – from behaviour and phenotype to transcriptome, proteome and microbiome – was also conserved in human participants from the UK Biobank. "Although these results highlight the differences between sexes that are preserved in circadian rhythms, they illustrate an apparent resistance of women to the adverse consequences of circadian misalignment," the authors conclude, to suggest that these findings "could have social implications, from the design of shift work schedules to the possibilities of coping with transmeridian flights."

  • United Kingdom
  • Genetics

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