Molecular basis and modelization of Diabetes and Obesity

Molecular pathophysiology of diabetes and obesity

Dr Annicotte Jean-Sébastien

Metabolic homeostasis is controlled amongst other mechanisms by transcriptional regulation involving transcription factors, cofactors and the transcription initiation machinery. Fine-tuned and non-permanent modulations of gene expression, in response to extra-cellular stimuli, through post-translational modifications such as histone methylation or acetylation, allow the cells to adapt to their environment. These mechanisms involve metabolites, transcription factors and enzymes able to recognize particular chromatin region (figure 1). However, this cellular response should be well orchestrated in order to respond correctly to metabolic perturbations, in a tissue and time specific fashion. Interestingly, during metabolic disease development, such as observed in diabetes and obesity, the expression of key gene controlling glucose and lipid metabolism is altered, leading to a non-coordinated response of these organs (liver, muscle, adipose tissues, pancreas). Although the molecular mechanisms are not well understood, it seems that several transcription factors and cofactors play a key role in this scenario. Moreover, epigenetic phenomena (acetylation, methylation) are also contributing to the development of metabolic diseases. Therefore, understanding how and why this dysregulation appears is a key question, and could open new therapeutic strategies to treat these diseases.

 Diapositive3Figure 1 : Metabolic adaptations to extra-cellular stimuli involve transcription factors, cofactors and epigenetic marks that will allow a coordinated response through the modulation of gene expression.

 

Dysfunctions of pancreatic β-cells, which produce insulin, as well as insulin target cells, such as hepatocytes, adipocytes or muscle cells are at the origin of pathological conditions, such as Diabetes Mellitus and cancer. Although diabetes etiology is complex, from gene mutations to environment impact, a common component of the two type of diabetes, i.e. immune type 1 and non-immune type 2 (T2D), is a decrease of β-cell mass, finally resulting in hyperglycemia and its subsequent deleterious consequences (figure 2).

Diapositive1Figure 2 : Type 1 and 2 diabetes etiology.

Therefore, a better understanding of the factors and mechanisms responsible for maintaining cell integrity is of high importance and could be of interest for the treatment of diabetes.

Our research program, conducted in EGID, CNRS UMR8199 headed by Pr P. Froguel, is focusing on the study of the molecular pathophysiology of diabetes and obesity and their modelizations (figure 3). By combining in vitro and in vivo approaches, we aim at elucidating the contributions of several transcription factors and cofactors to metabolic diseases such as diabetes, obesity and cardiovascular diseases.

Diapositive2Figure 3 : Modelization of diabetes and obesity by the use of, as an example, the Cre/LoxP technology.

Through the development of new animal models, our goal is to identify in different metabolic organs the role of these factors in maintaining metabolic homeostasis and their associated signaling pathways. These projects will help us to identify whether these factors could represent new targets for diabetes therapy, which is affecting 200-300 million people in the world.

 

Coordonnées :

Jean-Sébastien Annicotte, Ph.D.

 

Group Leader,

Molecular basis and modelization of Diabetes and Obesity Lab

 

European Genomic Institute for Diabetes

E.G.I.D. FR3508

Lille University-CNRS UMR 8199

 

Laboratoire de Recherche J & K

Faculté de Médecine – Pôle recherche

Boulevard du Professeur J. Leclercq

59045 Lille Cedex – France

 

Phone: 33.(0)3.20 97 42 10 (office)

Fax : 33.(0)3. 20 97 42 01

 

e-mail : jean-sebastien.annicotte@inserm.fr

Web site : http://www.egid.fr

http://www-good.ibl.fr

 

 

Financements :

– Agence Nationale pour la Recherche (Labex)

– Université Lille – Droit et Santé

– Association pour la Recherche sur le Diabète

– Lille Métropole – Communauté Urbaine

– Société Francophone du Diabète

– Laboratoires SERVIER