Circadian Rhythm and metabolism

Most biological processes follow an intrinsic day and night rhythm, orchestrated by an internal circadian clock. This genetic machinery consists of a core oscillator and multiple secondary loops that interact with each other, driving gene expression up and down throughout the day or in response to outside stimuli.
The expression of the core genes ARNTL, CLOCK, PER1, PER2, CRY1 and CRY2 as well as a host of functionally related genes of metabolism, myogenesis and cell cycle regulation such as NR1D1, RORA, MYOD1 and WEE1 is relevant to multiple exercise and health related areas of human physiology. This includes muscle (re-)growth, degree of hypertrophy, distribution of muscle fiber types, muscle ageing as well as diseases, phenotype changes and cancer conditions. However, the ways these genes might interact with each other throughout these different contexts have not yet been linked or contrasted with each other. This study analyzes the behavior of important circadian genes across multiple exercise- and health related conditions. As shown in previous literature, core circadian oscillator gene activity was often a main driving force in the response of circadian genes to various conditions. However, the present bioinformatic analysis also revealed potentially new overlapping and contrasting patterns of expression of these oscillator genes as well as other relevant genes involved in myogenesis, metabolism and the cell cycle. These results demonstrate how diversely circadian genes influence the physiological response of mammals in the context of health and exercise. I expect this study to instigate more sophisticated research toward the application of our knowledge of circadian rhythm genes to improve the timing of exercise and drug interventions in chrono-exercise and chronotherapy.

Keywords: circadian rhythm, chrono-exercise, bioinformatics

Previous studies have shown that genetic variants of the CLOCK gene have been associated with a risk of obesity. The aim of the study was to investigate the relationship of CLOCK SNPs o hypertension and coronary artery disease in Russian population. We genotyped 1139 individuals of Russian ethnicity including healthy subjects, patients with hypertension and patients with coronary artery disease. In addition, we studied effect of SNPs on the structure of the CLOCK mRNA using computational models. Blood pressure, total cholesterol (TC), triglycerides (TG), high-and low-density lipoprotein levels (mg/dl), glucose (mg/dl) and body mass index (BMI, kg/m2) were analyzed. There was no association between polymorphism in the BMAL1 gene with diseases given. Computational mRNA structure analysis has revealed changes in promoter and G2121A sites. Genetic variants of the CLOCK gene rs1801260, rs34789226, rs4865010 were positively associated with essential hypertension and coronary artery disease  in the sample of Russian population.

Ритмичное функционирование молекулярных циркадных часов в различных тканях и питание оказывают значительное влияние на продолжительность и качество жизни, а также скорость старения организмов. Известно, что масса тела коррелирует с экспрессией множества различных генов и риском летального исхода в различных возрастах. В настоящем исследовании предпринята попытка выявить закономерности в реализации генетической информации под давлением различных факторов, в частности способность эктопической экспрессии генов циркадных ритмов в жировом теле и мышцах влиять на массу тела в условиях, когда организм получает пищу с различными концентрациями белка. Использованы трансгенные линии Drosophila melano-gaster , несущие в промоторах генов циркадных ритмов ( cry , per , tim , clk , cyc ) UAS последовательности, усиливающие экспрессию, и линии, позволяющие индуцировать экспрессию тканеспецифичные GSG-311-2 (мышцы) и P{Switch1}106 (жировое тело). Измеряли на аналитических весах Mettler Toledo массу тела дрозофил и устанавливали корреляцию с инкрементами продолжительности жизни в ответ на сверхэкспрессию генов циркадных ритмов из ранее опубликованных данных. Установлена сильная корреляционная зависимость инкрементов массы тела и продолжительности жизни в случае сверхэкспрессии генов циркадных ритмов в жировом теле в условиях культивирования с повышенным содержанием белка, по Спирмену коэффициент корреляции составил 0.955. На основании полученных результатов и данных о высоком эволюционном консерватизме вовлеченных в процесс сигнальных путей (человеческие сигнальные пути эволюционно близки дрозофилиным каскадам) сделаны обобщения относительно негативных последствий использования высокобелковых диет в целях снижения массы тела на фоне нарушений циркадного ритма, которые широко распространены в мегаполисах.

The rhythmic functioning of the molecular circadian clock in various tissues and nutrition have a significant impact on the duration and quality of life, as well as the rate of aging of organisms. It is known that body weight correlates with the expression of many different genes and the risk of death at different ages. In the present study, an attempt was made to identify patterns in the implementation of genetic information under the pressure of various factors, in particular, the ability of ectopic expression of circadian rhythm genes in the fat body and muscles to influence body weight under conditions when the body receives food with different protein concentrations. We used transgenic Drosophila melanogaster lines carrying UAS sequences in promoters of circadian rhythm genes ( cry , per , tim , clk , cyc ) that enhance expression, and lines that make it possible to induce the expression of tissue-specific GSG-311-2 (muscles) and P{Switch1 }106 (fat body). Drosophila body weight was measured on a Mettler Toledo analytical balance and correlated with lifespan increments in response to overexpression of circadian rhythm genes from previously published data. A strong correlation dependence of body weight increments and life expectancy was established in the case of overexpression of circadian rhythm genes in the fat body under cultivation conditions with a high protein content; according to Spearman, the correlation coefficient was 0.955. Based on the results obtained and data on the high evolutionary conservatism of the signaling pathways involved in the process (human signaling pathways are evolutionarily close to Drosophila cascades), generalizations were made regarding the negative consequences of using high-protein diets to reduce body weight against the background of circadian rhythm disorders, which are widespread in megacities.

Disruption of circadian rhythms influences the pathogenesis of obesity, particularly with the basic regulation of food intake and metabolism. A link between metabolism and the circadian clock is the peroxisome proliferator-activated receptors (PPARs). The Neotomodon alstoni mouse, known as the “Mexican volcano mouse,” may develop obesity if fed a normo-caloric diet. This manuscript documents the changes in art of the hepatic lipid homeostasis in both sexes of lean and obese N. alstoni mice, comparing the daily changes in the BMAL1 clock protein, in regulators of lipid metabolism (PGC-1α, PPARα-γ, SREBP-1c, and CPT-1α) and in free fatty acid (FFA) and hepatic triacylglyceride (TAG) metabolites in light–dark cycles. Hepatic tissue and blood were collected at 5, 10, 15, 19, and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein. The results indicate that obesity affects daily changes in lipid metabolism and the BMAL1 profile in females considerably more than in males. These results suggest that the impact of obesity on lipid metabolism has important differences according to sex.