Nutrition Obesity & Risk of Thrombosis

Unité Mixte de Recherche  INSERM 1062 / INRA 1260 / AMU

 Micronutrients, adipose tissue and insulin resistance


Leader: Franck PEIRETTI

Regulation of insulin signaling by proteolytic cleavage of the insulin receptor.

Leader: Franck PEIRETTI


Insulin resistance is one of the main pillars of non-insulin-dependent diabetes. Mechanisms responsible of the progressive loss of insulin sensitivity may occur at different levels of insulin signaling, including the level of insulin receptor (IR).

Our group is interested in the proteolytic cleavages that affect IR in the development of insulin resistance. The first cleavage involving proprotein convertase is localized in the Golgi apparatus and generates the two IR subunits. Then, the IR ectodomain exposed at the cell surface is cleaved by a metalloproteinase and the newly generated transmembrane fragment is cleaved by the γ-secretase. Regulations and roles of these cleavages and generated fragments are poorly documented.

The hypothesis is that the proteolytic cleavages of the IR are actively involved in the regulation of insulin signaling.

The objective is to evaluate the significance of the IR cleavages (and generated fragments) in the regulation of insulin signaling in order to propose these steps of regulation as pharmacological targets to improve insulin sensitivity.



Proteolytic cleavage of IR


IR : insulin receptor


IRs : soluble fragment of insulin receptor


IR-icd : intracellular fragment of insulin receptor


PC : proprotein convertase


MP : metalloproteinase


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Micronutrients and adipose tissue.

Leader: Jean-François LANDRIER

 Nutritional deficiencies, especially deficiencies of some lipophilic micronutrients (vitamin A, vitamin D, vitamin E, carotenoids) might be associated and / or have an impact on the development of obesity and related diseases. Indeed, many epidemiological studies have reported an inverse relationship between plasma concentrations and / or consumption of micronutrients and incidence of obesity and type 2 diabetes.


Our working hypothesis is that the beneficial effects of these micronutrients may be mediated in part by the impact of these molecules on adipose tissue and especially on adipocyte. Indeed, these lipophilic molecules are mainly stored in adipose tissue, and they are able to modulate gene expression directly or via various nuclear receptor signaling pathways. Indeed, the microconstituants may modulate the expression pattern of cytokines and / or adipokines leading to an improvement or modification of the inflammatory state of adipose tissue, inducing various diseases associated with obesity including insulin resistance and metabolic inflammation.


This work is part of the nutrigenomics theme in our laboratory and Human Nutrition Department at INRA. Our research is based on a translational approach from cell to man through preclinical studies and focus on adipose tissue, whose involvement in obesity associated disorders is established.



Glucose transporter GLUT4 and type 2 diabetes.

Leader: Roland GOVERS

The very first hallmark of type 2 diabetes is the desensitization of liver, skeletal muscle and adipose tissue for insulin. This process, known as insulin resistance, is believed to be causal for malfunctioning of the pancreatic insulin-producing beta cells, finally leading to hyperglycemia. The glucose transporter that is mediating the insulin-regulated uptake of excess glucose from the blood by adipose tissue and muscle is GLUT4. In the non-stimulated (basal) state, GLUT4 is efficiently retained within intracellular compartments. The nature of this retention mechanism is currently unknown. Upon insulin stimulation, GLUT4 translocates to the cell surface via increased exocytosis and/or diminished retention, allowing the cell to take up glucose.

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Our team has two research goals. First, we aim to unravel in vitro the cellular trafficking pathways of GLUT4 and to establish how they are altered in insulin resistance. To this aim, we study various GLUT4 trafficking parameters in insulin responsive and insulin resistant cells, such as intracellular retention, organelle-specific dynamics, and the size of GLUT4's latent pool. For a large part of this, a unique novel technique is used that we have developed and that is filed for patent. This technique allows for a highly quantitative and kinetic analysis of multiple cellular trafficking steps of membrane proteins that at some point reach the plasma membrane.


In a more translational research line, multiple methodologies are exploited in order to find novel ways to modulate GLUT4 trafficking in vitro and in vivo. In particular, we focus on enhancing the appearance of GLUT4 at the cell surface via interference with the intracellular GLUT4 retention machinery. The methodologies that are used in this research line include a novel functional genetic screen. Our aim is to be able to increase cell surface GLUT4 levels independent of insulin, insulin signaling, and insulin resistance. The final goal of this research line is to be able to ameliorate glucose homeostasis in diabetes in vivo using GLUT4 as target molecule.


Taken together, we aim to both understand and modulate intracellular GLUT4 trafficking in insulin resistance and diabetes. Novel insights in these matters are essential in the quest to halt the detrimental complications that are associated with diabetes.



Ascorbic acid and cell differentiation.

Leader: Michel FONTÉS

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