Group ‘Nuclear receptors in circadian biology’ – Dr. Hélène Duez

 

Helene Duez, PhHeleneD

Contact info:

INSERM U1011 – Institut Pasteur de Lille-Université Lille Nord de France – EGID

1 rue Calmette, BP245, 59019 Lille

Tel: +33(0)3.2087.7793

Email : helene.duez@pasteur-lille.fr

 

 

Short biography:

During my PhD thesis, under the mentorship of Dr. Catherine Fiévet, I studied of the implication of nuclear receptors as regulators of complex gene networks to maintain whole-body energy balance and the integrity of the vascular wall. During my post-doctoral training with Dr. Gary Lewis at the University of Toronto, I have extended my expertise to the set-up of clinical studies and development of new tools to study metabolic fluxes in humans and mice. I have studied the hepatic and intestinal ipoprotein turn-over in diabetic patients. In 2008, I moved back to France with an INSERM Young Research Chair and established my team in the ‘Nuclear receptors, Diabetes and Cardiovascular Diseases’ Department and the European Genomic Institute for Diabetes (EGID). I obtained an independent tenure senior researcher/PI position at Inserm in 2009. My research interests are focused on the link between clock disruption and the development of metabolic and cardio-vascular diseases. More recently I have also developed a new line of research looking at the role of some clock components in skeletal muscle function, mass and metabolism.

I am a member of scientific societies such as the Société Française de Myologie (SFM), the Nouvelle Société Française d’Athérosclérose (NSFA), the Société Française de Diabète (SFD), the Society for Research on Biological Rhythms (SRBR) and the European Atherosclerosis Society (EAS).

To date, I have published 38 papers (h-index factor of 27 and average citation of 51/article) and I have been invited speaker at many prestigious international meetings, including the Gordon Research Conference, Keystone meetings, Embo meetings.

 

Keywords: Skeletal muscle, circadian clock, Rev-erb, metabolic and cardio-vascular disorders, myopathies

 

  • Research interest:

The biological clock is an ancient molecular circuitry that allows the organism to anticipate predictable daily changes and optimize its functions by gating them to the most relevant time of the day. The pervasive role of the clock in all facets of physiology is illustrated by the fact that disruption of the clock leads to numerous pathologies ranging from metabolic and cardio-vascular diseases to immune disorders or cancer.

However, in our modern “24/7” society, physical activity, food intake and light exposure are no longer restricted to daytime hours, sleep duration has been considerably reduced over the last century, and shiftwork is imposed by the economic demand, inducing circadian misalignment – the desynchronization between the intrinsic circadian rhythms (biological rhythms) and behavioral cycles – and putting millions of people at increased risk to develop severe diseases.

The mammalian molecular clock consists of several transcription factors. Among them, the nuclear receptors Rev-erbα and Rev-erbβ, and RORα are of special interest since they can be bound and activated by small molecules, hence representing pharmacological targets to re-align the clock.

Findings from our group and others have shed light on the role of Rev-erbα and Rev-erbβ in the circadian control of hepatic lipid and bile acid and glucose metabolism, muscle mitochondrial function and the inflammatory response of macrophages.

We are pursuing several lines of research, exploring the role of these clock components in skeletal muscle function, whole-body metabolism and their functions in the vascular wall. For these projects, we take a multidisciplinary approach combining original mouse models of gain- and loss-of-function, metabolic and immune phenotyping, primary cell culture, genome-wide gene expression and Rev-erb binding, with unconventional microfluidic co-culture, mathematic modelling and pharmacology.

Current projects:

  1. Role of the clock components Rev-erbα/β in muscle function

HD1Skeletal muscle harbors an endogenous clock, with 10% of cycling mRNAs and is able to respond to time cues (such as feeding and exercise). Intriguingly, not only metabolic genes but also the training response and exercise performance seem to be controlled by the clock system. Clock mutants display altered skeletal muscle function. For instance, we have shown that Rev-erbα controls skeletal muscle mitochondrial biogenesis and oxidative function through enhanced Lkb1-Ampk-Sirt1-Pgc1α signalling (Woldt, Sebti, et al., Nat.Med., 19, :1039–1046, 2013). As a result, Rev-erbα deficiency led to decreased skeletal muscle mitochondrial content and aberrant morphology of the remaining mitochondrial network, increased autophagy and compromised exercise capacity. This muscle disuse may have broad impact (muscle atrophy, dystrophy..).

In this project, we will further explore the role of the Rev-erbs in autophagy and the control of muscle mass and get molecular insights for these actions. We will also tackle the hypothesis that Rev-erbα/β affect myogenic progenitors and the response to muscle injury. Myopathies are characterized by repeated cycles of degeneration-regeneration, resulting in progressive muscle wasting and weakness, limited mobility, and, in the most severe cases, respiratory and/or heart failure. We aim at a better understanding of the potential of Rev-erb pharmacological activation for the treatment of muscle pathologies.

 

2. Role of Rev-erbα/β in metabolic homeostasis and the development of diabetes

 

HD2Lifestyle changes including exercise and a balanced diet are efficacious to prevent or ameliorate metabolic conditions such as obesity and type 2 diabetes (T2D). In skeletal muscle, mitochondrial dysfunction is often associated with the development of T2D. We have recently shown that Rev-erbα-deficient mice display dysfunctional mitochondria with aberrant morphology. However, the exact role of Rev-erbα/β in skeletal muscle metabolism is currently unknown, as well as their potential for health-promoting effects.

Our goal is to gain a better molecular understanding of the role of Rev-erbα/β in healthy and diseased muscle. This research might lead to the development of new treatments for T2D, especially for people with reduced mobility (morbid obesity, myopathies).

 

 

 

Fundings :

 

EFSDefsd, FFRD,frd, PHOTONICS 4 Society (North of France council CPER),region

FP7-Eurhythdia, eurrythdia, Labex EGID logo-EGID

 

 

  1. Role of Rev-erbα/β in the vascular wall & the development of vascular inflammation and atherosclerosis.

Atherosclerosis is a progressive disease of the vascular wall that accumulates lipids and fibrous components, leading to the recruitment of immune cells (monocytes/macrophages, lymphocytes, etc) and a sustained inflammation within the vascular wall. Atherosclerosis can lead to life-threatening conditions (myocardial infarction (MI), stroke). Known risk factors are high cholesterol levels, smoking, high blood pressure, diabetes and clock disruption. Indeed, shiftwork has been associated to increased risk of atherosclerosis and MI.

 

HD3In the past years, we have shown that Rev-erbα controls liver lipid metabolism as well as the macrophage response to a pro-inflammatory stimulus, suggesting a possible role for this nuclear receptor in the development of atherosclerosis. We are actively pursuing this line of research.

Image: accumulation of lipids (in red) in aortic sinus

 

Fundings: Fondation de France

fondation de france

 

 

  • Our Competences
  • In vivo models (circadian biology, exercise capacity, metabolic phenotyping, X-ray animal imaging, telemetry, measure of cardiovascular function, Crispr) – genetically-modified mouse models.
  • Muscle/vascular wall immunophenotyping (FACS and immunohistochemistry)
  • Nuclear receptors – pharmacology
  • Mitochondrial function (Oroboros, Seahorse)
  • Cell biology (primary cell culture eg satellite cells, monocyte/macrophages, etc..), myofiber isolation, cell synchronization, microfluidic co-culture (in collaboration with Dr. Vincent Senez)
  • Molecular biology (gene expression, DNA binding, real time qPCR)
  • Mathematic modeling of the clock (in collaboration with Prof. Marc Lefranc
  • Histology (incl. confocal microscopy)

 

  • Selected publications:

2016

Klionsky D.J., …, Duez H., … Lancel S., ….et al. Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd edition). Autophagy, 2016, 12(1):1-222

 

2015

Mayeuf-Louchat A., Staels B. and Duez H. ‘Skeletal muscle functions around the clock’. Diabetes, Obesity and Metabolism, 2015, 17 (Suppl1) : 39-46

Duez H. Troubles du métabolisme liés aux dérèglements des rythmes circadiens. Diabétologie Pratique, 2015. Wu C, Hussein MA, Shrestha E, Leone S, Aiyegbo MS, Lambert WM, Pourcet B, Cardozo T, Gustafson JA, Fisher EA, Pineda-Torra I, Garabedian MJ. Modulation of Macrophage Gene Expression via Liver X Receptor α Serine 198 Phosphorylation. Mol Cell Biol. 2015 Jun 1;35(11):2024-34.

 

2014

Duez H. Rythmes biologiques et santé métabolique. Dossier spécial MHDN à l’école – Correspondances en Métabolisme Hormone Diabète et Nutrition, 2014, 8 (8) : 204-211

Duez H. Gènes de l’horloge biologique et métabolisme: implications dans le diabète. Médecine des maladies Métaboliques, 2014, 8(4) : 396-401  http://www.em-consulte.com/en/article/929024

Marciniak C, Marechal X, Montaigne D, Neviere R, Lancel S. Cardiac contractile function and mitochondrial respiration in diabetes-related mouse models. Cardiovasc Diabetol. 2014 Aug 21;13:118.

Montaigne D., Maréchal X., Coisne A., Debry N., Modine T., Fayad G., Potelle C., El Arid J.M., Mouton S., Sebti Y., Duez H., Preau S., Remy-Jouet I., Zerimech F., Koussa M., Richard V., Nevière R., Edme J.L., Lefebvre P., Staels B. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation, 2014, 130 (7) : 554-64.

Makki K., Taront S., Molendi-Coste O., Bouchaert E., Neve B., Eury E., Lobbens S., Labalette M., Duez H., Staels B., Dombrowicz D., Froguel P., Wolowczuk I. Beneficial Metabolic Effects of Rapamycin are Associated with Enhanced Regulatory Cells in Diet-Induced Obese C57BL/6 Mice. PloS ONE, 2014, 9(4) : e92684. doi:10.1371/journal.pone.0092684.

Oger F., Gheeraert C., Benomar Y., Molendi-Coste O., Bouchaert E., Dombrowicz D., Pattou F., Duez H., Eeckhoute J., Staels B. and Lefebvre P. Cell-specific dysregulation of microRNAs expression in obese white adipose tissue. Journal of Clinical Endocrinology and Metabolism, 2014, 99(8) : 2821-33.

 

2013

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.

Duez H., Sebti Y. and Staels B. Horloges circadiennes et métabolisme: intégration des signaux métaboliques et environnementaux,  Médecine & Sciences, 2013, 29(8-9) : 772-777.

Pourcet B, Pineda-Torra I. Transcriptional regulation of macrophage arginase 1 expression and its role in atherosclerosis. Trends Cardiovasc Med. 2013 Jul;23(5):143-52.

Palud A, Marciniak C, Montaigne D, Marechal X, Ballot C, Hassoun SM, Decoster B, Neviere R, Lancel S. Macrophage migration inhibitory factor inhibition is deleterious for high-fat diet-induced cardiac dysfunction. PLoS One. 2013;8(3):e58718.

 

2012

Duez H., Cariou B. and Staels B. DPP-4 inhibitors in the treatment of type 2 diabetes. Biochemical Pharmacology, 2012, 83 : 823-832.

Lancel S, Montaigne D, Marechal X, Marciniak C, Hassoun SM, Decoster B, Ballot C, Blazejewski C, Corseaux D, Lescure B, Motterlini R, Neviere R. Carbon monoxide improves cardiac function and mitochondrial population quality in a mouse model of metabolic syndrome. PLoS One. 2012;7(8):e41836.

 

2011

Duez H. and Staels B. Circadian control of epigenetic modifications modulates metabolism. Circulation Research, 2011, 109(4) : 353-355.

Prawitt J., Abdelkarim M., Stroeve J.H., Popescu I., Duez H., Velagapudi V.R., Dumont J., Bouchaert E., van Dijk T.H., Lucas A., Dorchies E., Daoudi M., Lestavel S., Gonzalez F.J., Oresic M., Cariou B., Kuipers F., Caron S., Staels B. Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity. Diabetes, 2011, 60(7) : 1861-71.

Pourcet B, Feig JE, Vengrenyuk Y, Hobbs AJ, Kepka-Lenhart D, Garabedian MJ, Morris SM Jr, Fisher EA, Pineda-Torra I. LXRα regulates macrophage arginase 1 through PU.1 and interferon regulatory factor 8. Circ Res. 2011 Aug 19;109(5):492-501.

 

2010

Duez H. et Staels B. Les inhibiteurs de DPP-4: points communs et différences. Diabétologie Pratique, 2010, numéro de décembre.

Duez H. and Staels B. Nuclear receptors linking circadian rhythms and cardiometabolic control. Arteriosclerosis Thrombosis and Vascular Biology, 2010, 30(8) : 1529-1534.

Neviere R, Hassoun SM, Decoster B, Bouazza Y, Montaigne D, Maréchal X, Marciniak C, Marchetti P,Lancel S. Caspase-dependent protein phosphatase 2A activation contributes to endotoxin-induced cardiomyocyte contractile dysfunction. Crit Care Med. 2010 Oct;38(10):2031-6.

Lancel S, Qin F, Lennon SL, Zhang J, Tong X, Mazzini MJ, Kang YJ, Siwik DA, Cohen RA, Colucci WS. Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice. Circ Res. 2010 Jul 23;107(2):228-32.

 

  • Group members:

Group leader/PI

Dr. Helene DUEZ

Associate Professors, Univ Lille

Dr. Yasmine SEBTI

Dr. Steve LANCEL

Post-doctoral fellows

Dr. Benoit POURCET

Dr. Alicia MAYEUF-LOUCHART

PhD Students

Mathilde ZECCHIN

Alexis BOULINGUIEZ

Engineer/Research assistant

Lise FERRI

Stéphane DELHAYE

Quentin THOREL

Technician

Justine BEAUCHAMP

Flore DELSART

 

  • News:

Press releases:

- from Inserm, july 2013:

http://presse.inserm.fr/booster-les-capacites-respiratoires-des-muscles/8837/

Original article:  :  http://www.ncbi.nlm.nih.gov/pubmed/23852339

- Public conference for the ‘Diabetes Day’: ‘Bar des sciences : 300 millions de diabétiques, et moi, et moi, et moi….’, november 14th 2013, Lille, France:

- Initially launched in Australia, the international « my PhD in 3 minutes » competition is an exciting challenge requiring presentation skills. PhD students have 3 minutes to explain, to a non-specialist audience, their PhD project. Mathilde Zecchin has entered the ‘North of France’ final competition !

“Role of the nuclear receptors Rev-erbs in atherosclerosis development” :
- My group is involved in the annual Telethon-AFM supported ‘1000Chercheurs dans les écoles’ (‘1000 researchers in schools’) operation to stimulate high school students to initiate a career at University level in life sciences:

 

  • Open positions:

Applications for postdoctoral fellows and PhD program are welcome. If interested, please send a cover letter and an updated CV to Helene Duez (helene.duez@pasteur-lille.fr).