Asher Lab

Circadian Clocks and Metabolism

Research

Circadian rhythms, 24-hour cycles in behavior, physiology, and metabolism, are a fundamental feature of life on Earth. From cyanobacteria to humans, all light-sensitive organisms have evolved an internal clock that helps them anticipate daily changes in their environment.

In mammals, this system is coordinated by a central clock in the brain, which keeps time with the day-night cycle. But that's only part of the story as most cells in our body harbor their own “peripheral” clock. These peripheral clocks are synchronized with each other through various time-signals (such as food intake, oxygen levels, and temperature). Dis-synchrony between them and the environment is associated with a wide variety of pathologies from sleep apnea to metabolic syndrome and cancer.

Recent breakthroughs have uncovered an intricate interplay between circadian rhythms and metabolism. Our internal clocks not only influence our metabolism throughout the day but are also shaped by our metabolic state. Disruption of circadian rhythms is widely implicated in various metabolic diseases such as obesity, diabetes, and metabolic syndrome.

In our lab, we explore the intricate relationship between circadian biology and metabolism from the molecualr through cellular and whole organism level. We are interestd in understanding how this interplay contributes to health and disease. Through our research, we hope to uncover new insights that will inform treatments and lifestyle strategies for improving metabolic health.

Research page

Time-of-Day Control of Hypoxic Liver Response via BMAL1 and HIF1α

CO₂ and the Circadian Clock: Linking Gas Sensing and Lipid Metabolism

Oxygen and Circadian Clocks

Interactions between circadian clocks and exercise physiology

Oscillations in metabolite levels and metabolic pathways

Resetting of peripheral clocks

Unconventional Oscillations, Alternative Clocks

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Selected Publications

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome

Dandavate V., Bolshette N., Van Drunen R., Manella G., Bueno-Levy H., Zerbib M., Kawano I., Golik M., Adamovich Y. & Asher G. (2024) Cell Metabolism. 36, 9, p. 2038-2053.e5

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The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.

Circa-SCOPE: high-throughput live single-cell imaging method for analysis of circadian clock resetting

Manella G., Aizik D., Aviram R., Golik M. & Asher G. (2021) Nature Communications. 12, 1, 5903.

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Circadian clocks are self-sustained and cell-autonomous oscillators. They respond to various extracellular cues depending on the time-of-day and the signal intensity. Phase Transition Curves (PTCs) are instrumental in uncovering the full repertoire of responses to a given signal. However, the current methodologies for reconstructing PTCs are low-throughput, laborious, and resource- and time-consuming. We report here the development of an efficient and high throughput assay, dubbed Circadian Single-Cell Oscillators PTC Extraction (Circa-SCOPE) for generating high-resolution PTCs. This methodology relies on continuous monitoring of single-cell oscillations to reconstruct a full PTC from a single culture, upon a one-time intervention. Using Circa-SCOPE, we characterize the effects of various pharmacological and blood-borne resetting cues, at high temporal resolution and a wide concentration range. Thus, Circa-SCOPE is a powerful tool for comprehensive analysis and screening for circadian clocks resetting cues, and can be valuable for basic as well as translational research.

Clock proteins and training modify exercise capacity in a daytime-dependent manner

Adamovich Y., Dandavate V., Ezagouri S., Manella G., Zwighaft Z., Sobel J., Kuperman Y., Golik M., Auerbach A., Itkin M., Malitsky S. & Asher G. (2021) Proceedings of the National Academy of Sciences - PNAS. 118, 35, e210111511.

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Exercise and circadian biology are closely intertwined with physiology and metabolism, yet the functional interaction between circadian clocks and exercise capacity is only partially characterized. Here, we tested different clock mutant mouse models to examine the effect of the circadian clock and clock proteins, namely PERIODs and BMAL1, on exercise capacity. We found that daytime variance in endurance exercise capacity is circadian clock controlled. Unlike wild-type mice, which outperform in the late compared with the early part of their active phase, PERIODs- and BMAL1-null mice do not show daytime variance in exercise capacity. It appears that BMAL1 impairs and PERIODs enhance exercise capacity in a daytime-dependent manner. An analysis of liver and muscle glycogen stores as well as muscle lipid utilization suggested that these daytime effects mostly relate to liver glycogen levels and correspond to the animals feeding behavior. Furthermore, given that exercise capacity responds to training, we tested the effect of training at different times of the day and found that training in the late compared with the early part of the active phase improves exercise performance. Overall, our findings suggest that clock proteins shape exercise capacity in a daytime-dependent manner through changes in liver glycogen levels, likely due to their effect on animals feeding behavior.

Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals

Adamovich Y., Ladeuix B., Sobel J., Manella G., Neufeld-Cohen A., Assadi M. H., Golik M., Kuperman Y., Tarasiuk A., Koeners M. P. & Asher G. (2019) Cell Metabolism. 29, 5, p. 1092-1103.e3

Accepted version

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Daily rhythms in animal physiology are driven by endogenous circadian clocks in part through rest-activity and feeding-fasting cycles. Here, we examined principles that govern daily respiration. We monitored oxygen consumption and carbon dioxide release, as well as tissue oxygenation in freely moving animals to specifically dissect the role of circadian clocks and feeding time on daily respiration. We found that daily rhythms in oxygen and carbon dioxide are clock controlled and that time-restricted feeding restores their rhythmicity in clock-deficient mice. Remarkably, day-time feeding dissociated oxygen rhythms from carbon dioxide oscillations, whereby oxygen followed activity, and carbon dioxide was shifted and aligned with food intake. In addition, changes in carbon dioxide levels altered clock gene expression and phase shifted the clock. Collectively, our findings indicate that oxygen and carbon dioxide rhythms are clock controlled and feeding regulated and support a potential role for carbon dioxide in phase resetting peripheral clocks upon feeding. Adamovich et al. show that the daily regulation of oxygen consumption and carbon dioxide release is regulated by the circadian clock. Time-restricted feeding restores oxygen and carbon dioxide rhythms in clock mutants. Their findings also support a potential role for carbon dioxide in phase resetting of peripheral clocks upon feeding

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Asher Lab

Research

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new and exciting course by Prof. Gad Asher and Dr. Yaarit Adamovich

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QUADRIVIUM: music and science coming together

QUADRIVIUM: music and science coming together

Selected Publications

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome

Circa-SCOPE: high-throughput live single-cell imaging method for analysis of circadian clock resetting

Clock proteins and training modify exercise capacity in a daytime-dependent manner

Oxygen and Carbon Dioxide Rhythms Are Circadian Clock Controlled and Differentially Directed by Behavioral Signals