Our internal clock determines when we get tired, when we get hungry and when which genes are particularly active. In addition to the important influencing factor light, the hormone insulin also affects our circadian rhythm. How exactly it does this, researchers have now investigated for the first time on human samples. According to this, the insulin level in adipose tissue influences the activity of so-called clock genes, which control our internal clock. The regulation of our internal clock therefore also depends on when we eat our meals.
Our internal clock controls almost all physiological processes, such as metabolism, blood pressure and body temperature. In addition to the central internal clock in the brain, there are many subordinate clocks that can be found in every organ, tissue and cell in the body. The circadian rhythms are based on a close interplay of so-called clock genes, which generate a 24-hour rhythm via interleaved feedback loops. Studies have shown that our meal times can alter the circadian rhythm of various tissues and that eating at the wrong time increases the risk of obesity and type 2 diabetes. So far, however, little is known about the underlying mechanisms.
Insulin affects clock genes
A team led by Neta Tuvia from Charité Universitätsmedizin Berlin has now investigated how the increased insulin level after a meal affects the internal clock and which molecular processes play a role in this. To do this, the researchers first administered a set dose of insulin to 17 obese, non-diabetic men and then gradually gave them glucose until normal fasting blood sugar was achieved. “This method is usually used to determine insulin sensitivity,” explains co-author Olga Pivovarova-Ramich from the German Institute for Nutritional Research in Potsdam. “But it was also ideal for our research question because it enabled us to investigate the pure effects of insulin on human adipose tissue in vivo.”
Before the intervention and four hours afterwards, the researchers took adipose tissue samples from the test subjects, isolated the genetic material and determined the activity of various genes. Test subjects who had received a saline solution instead of insulin served as a comparison group. The result: “The expression of the most important clock genes, Per2, Per3 and NR1D1 in adipose tissue, was changed differently after insulin and saline infusion,” said the researchers. “This suggests an insulin-dependent regulation of the clock.”
Insight into the molecular mechanisms
To elucidate the molecular mechanisms responsible for this regulation, the Tuvia and her colleagues used human and animal fat cells, which they genetically modified: they linked a gene for the luminous enzyme luciferase to the clock key gene Per2. Whenever Per2 was active, the cells started to glow so that the researchers could follow the gene activity in real time. “We found that insulin causes a rapid and temporary increase in the activity of Per2 and thus changes the entire clock rhythm,” explains Tuvia.
In further molecular biological experiments, the researchers then identified those sections of the Per2 gene that are crucial for the insulin effect. They shortened the promoter piece by piece – the section of DNA that controls the expression of a gene – and discovered that the region between the 64th and 43rd base pair plays an essential role.
“Our results show for the first time how unfavorable meal times can disrupt our circadian rhythms and cause negative metabolic changes,” summarizes Pivovarova-Ramich. “This can also explain why nighttime eating has a particularly unfavorable effect on the metabolism.” The researchers assume that the mechanisms that lead to eating-related changes in the internal clock are even more complex and that other hormones and metabolites are involved. They want to deal with this in future studies.
Source: Neta Tuvia (Charité Universitätsmedizin Berlin) et al., Diabetes, doi: 10.2337 / db20-0910