Daniel MAUVOISIN

Circadian (about a day) rhythms are central in health and diseases. They originate from the molecular circadian clock, an evolutionary conserved mechanism that anticipates daily environmental changes. In mammals, a hypothalamic pacemaker adjusts basic physiological functions to the night/day cycles, but peripheral organs also have an intrinsic circadian clock. The liver circadian clock, for instance, fine-tunes metabolism by supporting metabolic flexibility, the capacity to adapt fuel oxidation to fuel availability. In fact, abnormal feeding schedules impose a circadian misalignment contributing to metabolic diseases, but the molecular links remain elusive.

Common presentations of metabolic diseases are overweight and Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD implicates multiple cellular and molecular signaling pathways mostly under the control of the circadian clock. To this end, we have provided evidence that to adjust metabolism across daily cycles of energy intake, the circadian clock and feeding control the mitochondrial network and its quality control mechanisms (mitochondrial dynamics). A fused mitochondrial network enhances bioenergetic efficiency whereas fission limits the oxidative stress during nutrient overload. Of note, loss of this mechanism through genetic disruption of the hepatic circadian clock triggers fatty liver disease.

Our overarching goal is to discover novel therapeutic targets in metabolic diseases using a chronobiological approach. NAFLD prevalence is skyrocketing and solutions are needed. Specific post-translational modifications (PTMs) represent novel pathophysiological mechanisms to explore.

Main objectives:

• To identify proteins regulated diurnally by PTMs.
• To discover the molecular link between these PTMs, diurnal mitochondrial dynamics and the molecular circadian clock.
• To explore therapeutic potential of modulating these PTMs in the context of metabolic disease.

• PhD in Biology at the University of Québec at Montréal (UQÀM) (Canada) :
  In 2011, I obtained a PhD in biology from UQÀM. My PhD research, performed in Pr. C. Mounier's lab, was focused on deciphering the hormonal and nutritional regulation of Stearoyl-CoA desaturase 1 (SCD1) gene expression. SCD1 is the rate-limiting enzyme of monounsaturated fatty acid synthesis. Its expression regulates membrane fluidity by fine-tuning the saturated to monounsaturated membrane fatty acids ratio. This regulation is also involved in metabolic diseases such as obesity and type II diabetes as well as in cancer.
• Post-Doc in University of Lausanne (UNIL) and Ecole Polytechnique Fédérale de Lausanne (Switzerland) :
  After focusing on the biology of SCD1, I wanted to explore a new way to apprehend metabolic regulation by coupling systems biology and chronobiological approaches. As a post-doctoral fellow, I first joined Pr. F. Gachon’s lab at the University of Lausanne and then the Computational Systems Biology lab of Pr. F. Naef at the Ecole Polytechnique Fédérale de Lausanne (Switzerland). My research characterised the diurnal hepatic proteome at wide scale at the cellular and nuclear level. It provided unprecedented resources into the diurnal regulatory landscape of the mouse liver nucleus and also highlighted the contribution of PTMs such as phosphorylation in the regulation of the rhythmic proteome. It also highlighted that feeding behaviour contributes to the rhythmicity of blood borne factors and depicted global oscillations in liver mass, hepatocyte size, and macromolecular content. Hence, my post-doc work contributed to enrich the chronobiology field while impacted both the circadian and the metabolic field.
• Joining INSERM 1087 in Nantes, (France) :
  In October 2019, I have been recruited as a Inserm CRCN to establish a research program to explore therapeutic potential of modulating diurnal post-translational modifications.