Cellular and Molecular Physiopathology of Obesity and Diabetes

Previous activities

The prevalence of obesity and type 2 diabetes is reaching epidemic proportion in industrialized countries. These pathologies increase the risk to develop cardiovascular, respiratory and renal diseases and certain cancers. Obesity and type 2 diabetes are characterized by an insulin resistance, i.e. a reduction in the metabolic effects of insulin in muscle, adipose tissue and liver. Our team has contributed for several years to clarify the cellular and molecular mechanisms by which insulin stimulates the transport of glucose in muscles and adipocytes and to identify the mechanisms responsible for the metabolic syndrome in obese or diabetics patients. More recently, we develop new research orientations to understand the mechanisms involved in the increased risk of cancers among obese patients. Our research program aims to identify new potential pharmacological targets against insulin resistance and to propose new prospects for a therapeutic approach of obesity, diabetes and of their associated complications.

Research Projects

The main aims of our studies are:
1) The study of the trafficking of the glucose transporter Glut4 and the alteration of this trafficking in insulin resistant states.
The glucose transporter Glut4 is expressed specifically in the adipose and muscular cells and allows the uptake of glucose by these cells, thus taking part in the fall of the glycemia in response to insulin. Glut4 recycles in a complex way between different cellular compartment and insulin stimulates Glut4 translocation from intracellular compartments towards the membrane plasma allowing for glucose uptake. Our goals are i) to define the molecular mechanisms which control Gut4 trafficking in response to insulin ii) to determine whether these processes are altered in obesity and diabetes iii) to determine if an alteration of these mechanisms can lead to the development of insulin resistance. By cellular and imagery approaches, we study the role of the GTPase of the Rab family and their effectors in Glut4 trafficking and in endocytosis. We develop models of genetically modified mice to determine the consequences of the invalidation of these proteins in the adipocyte on Glut4 trafficking, glucose homeostasis and the endocrine function of the adipose tissue. A better understanding of the molecular events which govern the intracellular traffic of Glut4 could allow the identification of new therapeutic targets to fight hyperglycemia and could lead to better understand the mechanisms involved in the protein sorting between different organelles.
2) The identification of the molecular mechanisms involved in the alteration of insulin action
Our goals are to identify the molecular mechanisms used by diabetogenic factors (hyperinsulinemia, inflammatory cytokines, fatty acid) in the development of insulin resistance in obesity and diabetes. We also search for other physiological factors leading to the development of an insulin resistance. There is a major focus on the role of serine/threonine kinases, serine phosphorylation events and the processes of ubiquitination in the negative regulation of insulin action. We study the implication of E3 ubiquitine ligases in the degradation of IRS1 (the major insulin receptor substrate) and in the regulation of insulin signalling. Using a variety of cellular models, genetically modified mice and pharmacological inhibitors, we study the role that various serine kinases and the changes in IRS1 phosphorylation or expression may play in the alteration of glucose metabolism and insulin signaling. For example, we have shown that knocking-out of the MAP kinase ERK1 results in mice that are protected against obesity and insulin resistance. We have also contributed to demonstrate a fundamental role of the serine phosphorylation of IRS1 in the down-regulation of insulin action. Part of these studies is funded by an European grant “Hepatic and adipose tissue function in the Metabolic Syndrome (http://www.hepadip.org)”.

3) The implication of the adipokines in tumorogenesis and angiogenesis.
Obesity is a risk factor for cancers development. Our researches focus on the relationship between the development of adipose tissue and cancer. Obesity is linked to an alteration of the endocrine function of the adipose tissue (modification of the pattern of adipokines secretion). Using cellular and animal models, we search for the implication of these adipokines in the growth of cancer cells and in tumor formation. We study the involvement of these adipokines in angiogenesis and the involved mechanisms (role in the secretion of angiogenic factors and in the function of the endothelials cells). Our studies should determine if an imbalance in the secretion of adipokines in obese patients is involved in the development of tumors in order to propose new therapeutic approaches.

 

Team Publications