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 at night, 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 discovered how the circadian clock controls muscle function and muscle mass through regulating calcium fluxes (Boulinguiez A., Duhem C., et al., JCI Insight 2022), mitochondrial biogenesis, metabolism and autophagy (Woldt, Sebti et al., Nature Medicine, 2013, 19(8): 1039-46; van Moorsel et al., Mol Metab 2016; Hansen et al., Sci Rep 2016; Mayeuf-Louchart, Thorel, et al., Sci Rep 2017; Wefers et al., PNAS, 2018).
  • We uncovered the essential role of glycogen storage and degradation by glycophagy for lipid droplets biogenesis during brown adipocytes differentiationin 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 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).
  • Our expertise: chronobiology/chronopharmacology, mouse metabolic phenotyping, mitochondrial respiration and calcium flux, immunophenotyping (FACS and immunohistochemistry), Imaging (Confocal microscopy, Lightsheet microscopy, Whole organ imaging), cell culture (incl primary cells)…

Projects

  • Study of the biological clock during muscle regeneration

Skeletal muscle has a remarkable capacity to regenerate following injury, a process that requires muscle stem cells activation, differentiation and fusion into regenerated fibers. Another important feature of muscle regeneration is the central role of inflammation which allows debris clearance and provides the optimal microenvironment for proliferation and differentiation of muscle stem cells. We are studying the role of the biological clock in muscle stem cells and immune cells during skeletal muscle regeneration.

Members involved: Yasmine Sebti, Alicia Mayeuf-Louchart, Quentin Thorel, Bettina Ram, Stéphane Delhaye, Mélissa Leriche

 

  • Study of the biological clock and the nuclear receptor Rev-erb-α in the vascular wall and atherogenesis.

Despite decades of lipid lowering drug (e.g. statins) use, prevention strategies and efforts in research, cardiovascular diseases, mainly caused by atherosclerosis, are still the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease of the vascular wall induced by the accumulation of lipid and immune cells leading to atherosclerotic plaque formation. Interestingly, alteration of circadian rhythm in shift workers accelerates atherogenesis. More than the obstruction of the vascular lumen, the most deleterious event is the rupture of the atheromatous plaque leading to the formation of a thrombus and ischemia of the downstream tissue (myocardial infarction, stroke…). The mechanisms and factors involved in plaque rupture remain poorly studied. We are interested in two major phenomena involved in plaque rupture: vascular calcification and intraplaque neovascularization. Our project aims at elucidating the molecular and cellular mechanisms involved in these phenomena and defining new therapeutic strategies to treat patients with coronary artery disease. Our transcriptomic data obtained in human and mouse allowed us to identify Rev-erbα as an important regulator of both phenomena. Using an integrated, multidisciplinary and cross-sectional approach, we aim to understand the role of this nuclear receptor in the different cell types of the vascular wall leading to inflammatory, angiogenic and pro-calcifying phenomena during atherogenesis.

Members involved: Benoit Pourcet, Lise Ferri, Cécilia Bellengier, Stéphane Delhaye, Christian Duhem

Collaborators: Paul Quax (Leiden, The Netherlands), Coralie Fontaine, Muriel Laffargue (Toulouse, France), David Smadja (Paris, France), Nicolas Venteclef, Jean-François Gautier (Paris, France), Jérome Vicogne (Lille, France), Jimmy Vandel (Bilille, Lille, France), Meryem Tardivel (Bicel, Lille, France), David Dombrowicz (Team 3, U1011), Joel Haas (Team 1, U1011)

 

  • Involvement of the alteration of the biological clock in the development of non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a pathology whose prevalence has increased considerably with type 2 diabetes (T2DM) and its metabolic consequences. A diet enriched in fatty acids and refined sugar is commonly accepted as a risk factor. In addition, numerous studies of shift workers have shown a correlation between alteration of the body clock and increased risk of developing metabolic diseases, such as T2DM. However, the molecular mechanisms behind these observations remain poorly understood. We study the impact of altered biological rhythms on the development of NAFLD and the molecular and cellular mechanisms involved.

Members involved: Aurore HEBRAS, Marie Bicharel, Stéphane Delhaye, Christian Duhem.

In collaboration with J Haas (team 1), D Dombrowicz (team 3), C Postic (Institut Cochin Paris), Hervé Guillou (Toxalim Toulouse), P Gourdy (Toulouse).

  • Investigating the role of glycogen metabolism in brown adipose tissue

The evolving global epidemic of obesity and type 2 diabetes has led to a growing interest in brown adipose tissue (BAT) as a novel therapeutic target for the treatment of metabolic diseases. BAT activity is inversely correlated with body mass index (BMI) and cold-induced thermogenesis is significantly lower in obese and overweight individuals. The cold-activated BAT metabolizes 20% of daily energy intake. Part of the glucose captured by brown adipocytes is stored as glycogen. However, little is known about the role of glycogen and its fate in brown adipocytes. We recently published a study characterizing brown adipocytes during embryonic development. Our results demonstrated the importance of the glycogen synthesis and degradation pathway, by glycophagy, in these cells, particularly for the control of multiple lipid droplet formation. We are currently studying glycogen metabolism in brown adipocytes in different physio-pathological models, in order to determine if this pathway can represent a potential target to improve BAT activity in the context of metabolic diseases and particularly type 2 diabetes.

Members involved: Alicia Mayeuf-Louchart, Mouna Amaouche-Accary

Expertise

Chronobiology/chronopharmacology, metabolic phenotyping, study of mitochondrial respiration (oxygraphy) and calcium flux, immunophenotyping (FACS/immunohistochemistry), imaging (confocal microscopy, light sheet microscopy, whole organ imaging), cell culture (lineages, primary cells),Crisp/cas9…, RNA scope, Development of models of genetic or environmental alteration of the clock

Transversal Projects

Development of new features on MuscleJ

(Collaboration: Dr. Anne Danckaert, Institut Pasteur, Paris)

MuscleJ is a bioinformatics tool allowing the automated quantification of many parameters that can be analyzed on immunofluorescence-labeled muscle sections. MuscleJ runs on ImageJ. Since its creation in 2018, new features continue to be developed.

 

Study of the role of the biological clock in skeletal muscle in Drosophila

(Collaboration: Dr. Pierre Dourlen, Pasteur Institute of Lille)

The molecular mechanisms controlling the generation of the circadian rhythm are present in all organisms and are relatively well conserved during evolution. As in mammals, the disruption of the biological clock in Drosophila (model Drosophila melanogaster) results in a decrease of lifespan. While the biological clock of skeletal muscle is well described in mammals, this is not the case in Drosophila. Our project aims to understand how the muscle clock functions in Drosophila skeletal muscle in order to identify evolutionarily conserved mechanisms.

Study of the interaction between peroxisomes and Hepatitis C virus replication complexes: Impact on cellular metabolism and oxidative stress

(Collaboration: Dr Yves Rouillé, CIIL, Pasteur Institute of Lille)

  Study of circadian rhythmicity in asthma

Collaboration: Dr. Anne Tsicopoulos, Pasteur Institute of Lille)

  Mathematical modeling of circadian rhythms

(Collaboration: Prof M. Lefranc, Univ Lille, CPER Photonics 4 society)

  Influence of age-related alteration of the biological clock on innate immunity in respiratory infectious diseases

(DREAM project in collaboration with Dr François Trottein, Pasteur Institute of Lille, Lille, Pr Serge Adnot, Mondor Institute of Biomedical Research, Paris, and Jimmy Vandel, Lille, France)

The DREAM project aims to determine the molecular and cellular mechanisms involved in the increased susceptibility of the elderly to pneumococcal infections, the first leading cause of bacterial pneumonia, in order to identify new therapeutic strategies in the treatment of these pathologies. One of the original avenues that the team is particularly interested in concerns the mechanisms controlled by the biological clock, whose robustness is known to be altered during aging and whose role is essential in the control of the innate immune response.

Role of the E2F1 pathway in the loss of function of pancreatic β-cells related to inflammation during aging

(MELODIE project in collaboration with Dr Jean-Sébastien Annicotte, Pasteur Institute of Lille, Lille)

MELODIE seeks to identify the molecular and cellular pathways involved in the inflammation-related dysfunction of pancreatic insulin-secreting β-cells during aging. The function and quantity of these cells decrease during aging, leading to the development of type 2 diabetes in the elderly. It has also been shown that inflammation of the pancreatic islets may be involved in these phenomena. MELODIE is particularly interested in the E2F1 pathway which plays a key role in the control of β-cell mass, and according to our data, in inflammation, during aging.

Role of influenza vaccine in atherogenesis

Influenza vaccination confers protection against systemic complications of inflammaging, especially atherosclerosis. The FLU-VASC translational project aims to identify mechanisms by which influenza vaccination confers protection against atherosclerosis and selectively limit inflammation, in mouse models and in a cohort of patients at high risk of atherosclerosis.

(Collaboration: Amal Aïdoud, Denis Angoulvant and Emmanuel Moise, University of Tours)

Interaction between the estrogen receptor and the circadian clock on endothelial cell function

(Collaboration: Coralie Fontaine, Françoise Lenfant, Jean-François Arnal, Toulouse, France)

Role of the circadian clock in gout

(Collaboration: Hang-Korng EA, Paris, France; Megan Leask, Birmingham, USA)

Members

Hélène DUEZ
Inserm Senior Researcher, PI
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

Marie BICHAREL LECONTE
Engineer                                                   ORCID number : 0000-0002-7660-0913

Mélissa LERICHE
Postdoctoral fellow                              ORCID number : 0000-0002-9028-9957

 

Mouna AMAOUCHE-ACCARY
PhD student                                            ORCID number : 0000-0001-7829-9549

Cécilia BELLENGIER
PhD student

Aurore HEBRAS
PhD student

Quentin THOREL
Postdoctoral fellow

Bettina RAM
PhD student

Margaux LEDUC
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

Biological clock; Circadian rhythms; Metabolism; Inflammation; Muscle; Metabolic and cardiovascular diseases; Myopathies; Liver; Immune system; Mitochondria; Angiogenesis; Vascular calcification; Brown fat; Glycophagy; Muscle regeneration; Muscle stem cells

Team contact

Hélène Duez
Inserm researcher

helene.duez@inserm.fr