A First Atlas of the Circadian Metabolism


A team from the Inserm/University of California International Joint Research Unit, located in Irvine in the USA, has recently produced - in mice - an atlas of metabolic regulation over 24 hours.  Now available for access by the entire scientific community, this atlas already shows that a high-fat diet strongly disrupts organ function, probably by desynchronizing their biological clocks.

The biological clock, which controls our circadian rhythm is infinitely more complex than scientists a decade ago used to think. A central clock imposes a rhythm of about 24 hours on the body, which controls many functions in a cyclical manner: sleeping, waking, mood, digestion, etc. However, in order to optimize each of its functions, the body is also equipped with peripheral clocks in the various organs (retinas, liver, muscles, etc.). They refine the regulation and improve the efficacy of each of these organs, in order to adapt to external and internal constraints. Therefore, someone who works nights is able to maintain good visual acuity even if his central biological clock dictates that he give his retinas a rest.

Each clock is equipped with synchronizers: the central clock is aligned primarily with light exposure and gives the principal rhythm to the peripheral clocks, but other signals - many of which remain to be discovered - also inform the various peripheral clocks on the state in which they must find themselves at any given time. So we are talking about a complex system.

Metabolism monitored in various tissues

For a deeper understanding of the circadian regulation of the metabolism, Paolo Sassone-Corsi and his team from the Inserm/University of California (Irvine, United States) International Joint Research Unit, have created an atlas of metabolic regulation over 24 hours, in mice. This atlas is available for access by the entire scientific community.

This was done by taking samples from the animals every 4 hours, and by measuring hundreds of metabolites (fatty acids, amino acids, sugars, peptides, vitamins and nucleotides) in the cells of tissues and biological fluids: two regions of the brain, muscle, adipose tissue, liver, serum and sperm. "Analyzing these compounds gives us information on many metabolic pathways", explains Sassone-Corsi. As such, maps were drawn up for each tissue, representing the concentration of all these compounds at various times of the day and night.

With these, major divergences in organ function were observed at equivalent times, but also strong similarities with synchronous oscillations of some metabolites in various organs. "It appears evident that the organs communicate among themselves in order to coordinate their functioning. Now we need to find what these communication pathways are and what happens if we disrupt them", explains Sassone-Corsi.

Clocks deregulated by a high-fat diet

Next, the researchers fed the mice a high-fat diet and started the experiment again. It was then that they noted that the rhythms previously observed were totally disrupted, in all the tissues. The distribution of the metabolites in the various cell types noted under normal conditions was not at all reproducible with a high-fat diet. It resembled a vast cacophony. "This diet, which we can liken to an excessively rich Western diet, appears to desynchronize the peripheral clocks among themselves. This is expressed by a metabolic modification, independent in each tissue and which cannot be imagined not to impact health", concludes Sassone-Corsi. What remains to be elucidated is how these deregulations occur and what impacts they have on the body.

These laboratories helping to raise Inserm’s profile abroad

The Epigenetic and metabolic control of cellular plasticity Inserm unit (Unit 1233) currently directed by Paolo Sassone-Corsi was created in 2008 by Prof. Emiliana Borrelli. A joint research unit made up of Inserm and the Center for Epigenetic and Metabolic Control of cellular plasticity of the University of California, Irvine, it has the originality of being located close to Los Angeles in the USA.

Along with the International/European Associated Laboratories (IAL/EAL) and the joint research groups, the international joint research units make it possible to form unprecedented collaborations and establish Inserm’s reputation abroad, with major scientific findings.

To find out more about Inserm’s international cooperation tools

Source : KA Dyar et coll. Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks. Cell dated September 6, 2018. DOI:https://doi.org/10.1016/j.cell.2018.08.042