Circadian cycles impact almost every element of our biology, and Paolo Sassone-Corsi, Ph.D., Director of the Center for Epigenetics and Metabolism and the Donald Bren Professor at the University of California, Irvine, has been examining the effects on metabolic functions for nearly three decades. In fact, a system-wide coordination and communication between clocks has been revealed. Understanding the intricate communication between cellular rhythms and biological processes will aid in greater understanding of metabolic disorders and the pharmacological interventions to support those patients.

Dr. Sassone-Corsi’s research has focused on unraveling how epigenetics is critical for healthy lifespan, wellbeing, appropriate circadian sleep cycles, aging and disease prevention. His formative discoveries have changed the circadian clock paradigm, proving the existence of secondary clocks that control peripheral tissues throughout the body.

The Sassone-Corsi Laboratory has charted new territory in revealing how circadian clocks communicate to synchronize cellular processes. The research led by Dr. Sassone-Corsi links epigenetics and metabolism in a vast array of biological systems. Dr. Sassone-Corsi has published several hundred peer-reviewed articles, many in the highest impact science journals. He also has received an expansive list of prestigious international scientific awards for his innovative work.

Recent work by the Sassone-Corsi lab has delved deep to understand the impacts on metabolic diseases, therapeutic interventions, exercise and even health of aging skin.

The link between circadian rhythm and metabolic disease

Several recent studies by the Sassone-Corsi team highlight the effect of nutritional abundance on circadian metabolism and demonstrate its relevance to the development and management of metabolic disease.¹ Building on their previous work, they used an integrated systems biology approach to examine several tissues in the context of energy balance. By comparing the patterns of metabolism under a normal chow diet with conditions of nutrient stress imposed by a high fat diet (HFD), they assembled a spatial and temporal atlas of circadian mouse metabolism. The atlas maps hundreds of circadian metabolites, revealing the metabolic connections that control daily oscillations in processes that are often mediated by distal organ systems. Furthermore, the study showed that external factors such as chronic nutrient stress can alter communication and coordination between tissue clocks, resulting in metabolic changes associated with pathology.

Global metabolomics detected a wide range of metabolite classes from 8 tissue types (i.e., serum, liver, skeletal muscle, brain, brown and white fat, and sperm). Alterations in the relative abundance of several metabolites were characteristic of known tissue-specific pathology. For example, carbohydrates comprised 53% of total altered liver metabolites of mice fed normal chow compared with only 8% in the HFD group. Lipid metabolites exhibited an inverse proportion, with 11% altered in mice on normal chow versus 52% in HFD-fed mice. The accumulation of lipids in liver relative to carbohydrates is suggestive of HFD-induced hepatic steatosis and may have relevance to the progression of NASH. A similar shift in lipid accumulation in skeletal muscle, a prominent glucose sink, suggests the potential for development of insulin resistance. Supporting these observations, several epidemiological studies have correlated an increased risk for insulin resistance and fatty liver with night shift work.^2,3

To create a visual atlas of the metabolites under study, the group applied algorithms that plotted the significant temporal correlations according to metabolite class and tissue type. The resulting atlas revealed both temporal and tissue-specific signatures of metabolic pathways over the 24-hour cycle. When examining correlations according to metabolite class, serum lipids showed the greatest degree of synchronization with other metabolites under normal chow, consistent with a role for the vasculature in integrating biochemical networks. However, under HFD nutrient stress, these correlations were lost or significantly reduced, affirming the impact of energy balance on circadian misalignment.

Bench to bedside: circadian clock considerations

In addition to elucidating key spatial and temporal elements of energy metabolism, the work by the Sassone-Corsi team provides a model for examining the relationship between other external factors and normal coherent networks across tissues. Their results highlight the importance of translational science and how observed differences in metabolism may be converted to clinical interventions. The proposed model is not limited to examining the effect of nutritional behavior on metabolic disease, or other behavioral interventions such as exercise. Integrated analysis of the circadian metabolome using tools like Metabolon’s global metabolomics platform offers potential for further discovery in disease pathways to reveal novel biomarkers and therapeutic targets, as well as fine-tuning clinical diagnostics.

Diagnostic measures and drug dosing are typically scheduled irrespective of circadian metabolism. Constraints of the clinician’s timetable, ensuring appropriate time intervals between medication doses, or the requirements of sample collection (e.g., fasting plasma or morning urine) dictate scheduling rather than coordinating with biological clocks. Many commonly prescribed drugs work by targeting the products of circadian genes, and since their half-lives are often less than 6 hours, timing of administration might have a significant impact on their action or influence potential side effects.⁴ Metabolite comparisons across multiple tissues may provide insight that has been missing from studies of single biomarkers that represent only one tissue at a specific time point of the circadian metabolome.

The relationship between coordination of peripheral clocks and pathology remains mostly unknown, but the circadian atlas presented by Dyar and Lutter, et al. demonstrates how global metabolomics is beginning to fill this information gap. Exploiting known oscillations might permit actionable insights including optimization of other external behaviors, improving the accuracy of diagnostics, and targeting specific time points to administer therapeutics. In the future, this same approach could be used on human samples to unlock biological discoveries hidden within the temporal dysregulation of metabolic processes and provide insights to develop personalized chronotherapy.

Effects of exercise on energy metabolism

• https://www.eurekalert.org/pub_releases/2019-04/uoc–nus041719.php
• https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(19)30183-4

The effect of circadian rhythm on the health of aging skin

In 2019, Estee Lauder companies leveraged metabolomics, with circadian rhythm, to deepen its knowledge of skin conditions to improve the health of aging skin. The work leveraged Metabolon’s global metabolomics approach to understand the impact of circadian rhythm working with Dr. Sassone-Corsi and his team. The findings revealed that with proper treatment, the rhythmicity for many of the skin metabolites can be reestablished, helping to synchronize skin with its natural youthful rhythm of dynamic repair.

In the graph, the blue line denotes young skin, the red is for mature, and the green represents mature skin treated with Estee Lauder’s night repair. These are powerful metabolomic insights that are being applied by Estee Lauder Companies to formulate products that can address and improve optimal skin processes, leading to younger-looking skin.

Dr. Sassone-Corsi’s insightful works into the circadian rhythm have been fueled by metabolomics revealing numerous findings to support health and disease management.

References:

1. Asher G, Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell. 2015; 161:84-92. doi: 10.1016/j.cell.2015.03.015
2. Guo Y, Rong Y, et al. Shift work and the relationship with metabolic syndrome in Chinese aged workers. PloS One. 2015; 0120632. doi: 10.1371/journal.pone.0120632
3. Konturek PC, Brzozowski T, Konturek SJ. Gut clock: implication of circadian rhythms in the gastrointestinal tract. J Physiol Pharmaco. 2011; 62:139-150.
4. Zhang R, Lahens N, et al. A circadian gene expression atlas in mammals. PNAS. 2014; 111:16219-16224. doi: 10.1073/pnas.1408886111