Nuclear receptors and circadian rhythms in pathophysiology

Team 5 – INSERM U1011 – Lille University – CHU Lille – Institut Pasteur de Lille

équipe 5 recepteurs nucléaires microscope

Presentation

The biological clock plays crucial roles in several aspects of physiology. For instance, it generates circadian rhythms in sleep patterns, blood pressure, the immune response and metabolism. Clock disruption, as seen in shiftwork, frequent jetlag, and extended light exposure and feeding period, increases the risk of developing a myriad of pathologies including metabolic (obesity, type 2 diabetes, NASH), inflammatory and cardio-vascular (atherosclerosis, myocardial infarction) disorders. Focusing on the drug-targetable clock components and nuclear receptors Rev-erbs and RORs, we aim at unraveling the cellular and molecular mechanisms by which the clock impacts metabolism and inflammation in several pathophysiological contexts, particularly metabolic, cardio-vascular and muscle diseases. We aim at determining whether/how pharmacological modulation of these nuclear receptors restores circadian rhythmicity and ameliorates these pathological conditions. Besides interactions developed with other teams of UMR1011, our team is engaged in local and (inter)national collaborations to complement our expertise and to perform translational studies.

Highlights

  • We uncovered the essential role of glycogen storage and degradation by glycophagy for lipid droplets biogenesis during brown adipocytes differentiation in vivo (Mayeuf-Louchart et al., Cell Reports 2019).

  • We discovered that Rev-erb-α controls the secretion of cytokines by macrophages through rhythmic repression of the NLRP3 inflammasome, identifying Rev-erb-α as a major player in the circadian immunity (Pourcet, et al., Gastroenterology, 2018).

  • We showed diurnal variations in perioperative myocardial injury in patients undergoing aortic valve replacement (Montaigne et al., Lancet, 2018).

  • We established a mathematical model of clock disruption associated with metabolic disorders (Woller et al. Cell Reports, 2016; Furlan et al., PNAS, 2019).

  • We discovered how the circadian clock controls muscle mitochondrial biogenesis and function, and autophagy (Woldt, Sebti et al., Nature Medicine, 2013, 19(8): 1039-46).

  • In a collaborative study, we published the first evidence of a circadian rhythmicity in mitochondrial function in human myotubes from healthy, but not diabetic, patients (van Moorsel et al., Mol Metab 2016; Hansen et al., Sci Rep 2016). Circadian misalignment compromises muscle insulin sensitivity (Wefers et al., PNAS, 2018), revealing a novel mechanism for the increased risk of type 2 diabetes observed in shiftworkers.

  • We showed that Rev-erbα controls muscle mass and is a promising target to limit muscle loss (Mayeuf-Louchart, Thorel, et al., Sci Rep 2017).

  • We developed MUSCLE J, a new bioinformatic tool to quantify muscle fiber cross-section area and typing, the number and localization of nuclei, muscle stem cells and endothelial cells (Mayeuf-Louchart, et al. Skeletal Muscle, 2018).

  • We developed in vivo models of genetic (including using Crispr/Cas9) and environmental clock alteration.

  • Our expertise: chronobiology/chronopharmacology, mouse metabolic phenotyping, mitochondrial respiration and calcium flux (Lancel et al., JCI Insight 2018), immunophenotyping (FACS and immunohistochemistry), Imaging (Confocal microscopy, Lightsheet microscopy, Whole organ imaging), cell culture (incl primary cells)…

  • Current fundings: FRM, SFD, FFC, ANR, Labex EGID, AFM-téléthon, Feder, CPER, Fondation de France.

Members

Hélène DUEZ
DR2 Inserm, group leader
ORCID number : 0000-0002-4130-7987

Benoit POURCET
Associate prof
ORCID number : 0000-0002-6758-5467

Yasmine SEBTI
Associate prof
ORCID number : 0000-0002-1813-810X

Alicia MAYEUF-LOUCHART
Inserm researcher
ORCID number : 0000-0002-3787-7450

Stéphane DELHAYE
Engineer
ORCID number : 0000-0001-9438-6730

Christian DUHEM
Engineer
ORCID number : 0000-0003-0931-3815

Lise FERRI
Engineer and PhD student
ORCID number : 0000-0003-1981-4250

Marion GIMENEZ
Engineer

Thara JAWORSKI
Engineer

Marine ANDRES
PhD student

Cécilia BELLENGIER
PhD student

Aurore HEBRAS
PhD student

Quentin THOREL
PhD student

Bettina RAM
Master student

Publications

Woldt E.*, Sebti Y.*, Solt L.A., Duhem C., Lancel S., Eeckhoute J., Hesselink M.K.C., Paquet C., Delhaye S., Shin Y., Kamenecka T.M., Schaart G., Lefebvre P., Nevière R., Burris T.P., Schrauwen P., Staels B., Duez H.
Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.
Nature Medicine, 2013, 19(8) : 1039-1046.

Montaigne D., Maréchal X., Modine T., Coisne A., Mouton S., Fayad G., Ninni S., Klein C., Ortmans S., Seunes C., Potelle C., Berthier A., Gheeraert C., Piveteau C., Deprez R., Eeckhoute J., Duez H., Lacroix D., Deprez B., Jegou B., Koussa M., Edme JL., Lefebvre P., Staels B.
Day-time variation of peri-operative myocardial injury in cardiac surgery and its prevention by Rev-erbɑ antagonism: a single-centre propensity-matched cohort study and a randomised study.
The LANCET, 2018, 391:59-62

Lancel S, Hesselink MK, Woldt E, Rouillé Y, Dorchies E, Delhaye S, Duhem C, Thorel Q, Mayeuf-Louchart A, Pourcet B, Montel V, Schaart G, Breton N, Picquet F, Briand O, Salles JP, Duez H, Schrauwen P, Bastide B, Bailleul B, Staels B, Sebti Y.
Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity.
JCI Insight, 2018, 3(9). pii: 98081. doi: 10.1172/jci.insight.98081

Pourcet B*, Zecchin M*, Ferri L, Beauchamp J, Sitaula S, Billon C, Delhaye S, Vanhoutte J, Mayeuf-Louchart A, Thorel Q, Haas J, Eeckhoute J, Dombrowicz D, Duhem C, Boulinguiez A, Lancel S, Sebti Y, Burris T, Staels B and Duez H.
Nuclear Receptor Subfamily 1 Group D Member 1 (Rev-erb-α) Regulates Circadian Activity Of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice.
Gastroenterology, 2018, 154(5):1449-1464.e20

Mayeuf-Louchart A, Lancel S, Sebti Y, Pourcet B, Loyens A, Delhaye S, Duhem C, Beauchamp J, Ferri L, Thorel Q, Boulinguiez A, Zecchin M, Dubois-Chevalier J, Eeckhoute J, Vaughn LT, Roach PJ, Dani C, Pederson BA, Vincent SD, Staels B, Duez H.
Glycogen Dynamics Drives Lipid Droplet Biogenesis during Brown Adipocyte Differentiation.
Cell Rep. 2019, 29(6):1410-1418.e6. doi: 10.1016/j.celrep.2019.09.073. PMID: 31693883


Keywords

Clock ; Circadian rhythms ; Metabolism ; Inflammation ; Metabolic and cardio-vascular disorders ; Myopathies ; Skeletal muscle ; Liver ; Vascular wall ; Immune cells ; Mitochondria

Team contact

Hélène Duez
Inserm researcher

helene.duez@inserm.fr