Combined physical exercise reverses the reduced expression of Bmal1 in the liver of aged mice.

Aging can modify the morphology and function of the liver, such as generating a decrease in the mitochondria content, autophagy, and cell senescence. Although exercise training has several beneficial effects on hepatic metabolism, its actions on autophagy processes, mitochondrial function, and cellular senescence need to be more widely explored. The present study verified the effects of aging and exercise on hepatic circadian markers, autophagy, and mitochondria activity in 24-month-old mice with a combined exercise training protocol. In addition, we used public datasets from human livers in several conditions and BMAL1 knockout mice. C57BL/6 mice were distributed into Control (CT, young, 6-month-old mice), sedentary old (Old Sed, sedentary, 24-month-old mice), and exercised old (Old Ex, 24-month-old mice submitted to a combined exercise training protocol). The exercise training protocol consisted of three days of endurance exercise - treadmill running, and two days of resistance exercise - climbing a ladder, for three weeks. At the end of the protocol, the liver was removed and prepared for histological analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting technique, and oxygen consumption. Heatmaps were built using a human dataset and Bmal1 knockout samples. In summary, the Old Sed had reduced strength, coordination, and balance, as well as a decrease in Bmal1 expression and the presence of degenerated liver cells. Still, this group upregulated the transcription factors related to mitochondrial biogenesis. The Old Ex group had increased strength, coordination, and balance, improved glucose sensitivity, as well as restored Bmal1 expression and the mitochondrial transcription factors. The human datasets indicated that mitochondrial markers and autophagy strongly correlate with specific liver diseases but not aging. We can speculate that mitochondrial and autophagy molecular markers alterations may depend on long-term training.

Central administration of REV-ERBα agonist promotes opposite responses on energy balance in fasted and fed states.

The REV-ERBα receptor has a recognised role in the regulation of the circadian rhythm system. However, recent evidence suggests that it also contributes to energy balance regulation. Both expression and function of REV-ERBα can be influenced by the energy status of the body. Considering the possibility of the involvement of REV-ERBα in the regulation of energy balance, which is critically regulated by the hypothalamus, and based on the impact of intermittent fasting, the present study evaluated the effects of central administration of REV-ERBα agonist on energy balance in rats exposed to 24 hours of fasting or ad lib. feeding conditions. Initially, 24-hour fasted rats received an acute i.c.v. administration of agonist at doses of 1, 5, 10 or 15 µg per rat and feed efficiency was evaluated. Because 10 µg was a sufficient dose to affect feed efficiency, subsequent experiments used this dose to assess effects of agonist on the following parameters: energy expenditure induced by physical activity and locomotor activity, time spent in physical activity over 24 hours, and glucose and insulin tolerance. In fasted rats, the agonist promoted increased food intake and feed efficiency, with a greater body weight gain associated with less time spent in locomotor activity, suggesting a reduction in energy expenditure induced by physical activity. Furthermore, a reduction in glucose tolerance was noted. By contrast, free-fed rats exhibited reduced food intake and feed efficiency with decreased body weight gain along with an increase in locomotor activity and physical activity-dependent energy expenditure. Thus, i.c.v. administration of REV-ERBα agonist regulates energy balance depending on the energy status of the organism; that is, it promotes a positive energy balance in the fasted state and a negative energy balance in the fed state. These results may be useful in understanding the underlying mechanisms of energy balance disorders and intermittent fasting for body weight control.

Role of the clock gene Rev-erbα in metabolism and in the endocrine pancreas.

Several hormones are regulated by circadian rhythms to adjust the metabolism to the light/dark cycles and feeding/activity patterns throughout the day. Circadian rhythms are mainly governed by the central clock located in the suprachiasmatic nucleus but also by clocks present in peripheral organs, like the endocrine pancreas. Plasma glucose levels and the main pancreatic hormones insulin and glucagon also exhibit daily variations. Alterations in circadian rhythms are associated with metabolic disturbances and pathologies such as obesity and diabetes. The molecular components of central and peripheral clocks and their regulatory mechanisms are well established. Among the different clock genes, Rev-erbα is considered one of the key links between circadian rhythms and metabolism. Rev-erbα is a critical part of a negative feedback loop in the core circadian clock and modulates the clock oscillatory properties. In addition, Rev-erbα plays an important role in the regulation of lipid and glucose metabolism, thermogenesis, adipocyte and muscle differentiation as well as mitochondrial function. In the endocrine pancreas, Rev-erbα regulates insulin and glucagon secretion and pancreatic ß-cell proliferation. In the present review, we discuss all these subjects and, particularly, the role of the clock gene Rev-erbα in the endocrine pancreas.