Team 7: Jean-François Tanti/ Mireille Cormont
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 (”.

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.


Major Publications


Regazzetti C, Dumas K, Lacas-Gervais S, Pastor F, Peraldi P, Bonnafous S, Dugail I, Le Lay S, Valet P, Le Marchand-Brustel Y, Tran A, Gual P, Tanti JF, Cormont M, Giorgetti-Peraldi S. Hypoxia inhibits Cavin-1 and Cavin-2 expression and down-regulates caveolae in adipocytes. Endocrinology. 2015 Mar;156(3):789-801

Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, Laurent K, Larbret F, Malavaud B, Cormont M, Lemichez E, Cuvillier O, Tanti JF, Bost F. Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells. Mol Cancer Ther. 2015 Feb;14(2):586-96.


Ceppo F, Jager J, Berthou F, Giorgetti-Peraldi S, Cormont M, Bost F, Tanti JF.
[Implication of MAP kinases in obesity-induced inflammation and insulin
resistance]. Biol Aujourdhui. 2014;208(2):97-107.2014 Sep 8. French. .

Tannour-Louet M, York B, Tang K, Stashi E, Bouguerra H, Zhou S, Yu H, Wong LJ, Stevens RD, Xu J, Newgard CB, O'Malley BW, Louet JF. Hepatic SRC-1 activity orchestrates transcriptional circuitries of amino acid pathways with potential relevance for human metabolic pathogenesis. Mol Endocrinol. 2014 Oct;28(10):1707-18.

Ceppo F, Berthou F, Jager J, Dumas K, Cormont M, Tanti JF. Implication of the Tpl2 kinase in inflammatory changes and insulin resistance induced by the interaction between adipocytes and macrophages. Endocrinology. 2014 Mar;155(3):951-64.


Perrin L, Lacas-Gervais S, Gilleron J, Ceppo F, Prodon F, Benmerah A, Tanti JF, Cormont M. Rab4b controls an early endosome sorting event by interacting with the γ-subunit of the clathrin adaptor complex 1. J Cell Sci. 2013 Nov 1;126

Tanti JF, Ceppo F, Jager J, Berthou F. Implication of inflammatory signaling pathways in obesity-induced insulin resistance. Front Endocrinol (Lausanne). 2013 Jan 8;3:181.

Ben-Sahra I, Dirat B, Laurent K, Puissant A, Auberger P, Budanov A, Tanti JF, Bost F. Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death. Cell Death Differ. 2013 Apr;20(4):611-9.


Regazzetti C, Dumas K, Le Marchand-Brustel Y, Peraldi P, Tanti JF, Giorgetti-Peraldi S. Regulated in Development and DNA Damage Responses -1 (REDD1) Protein Contributes to Insulin Signaling Pathway in Adipocytes. PLoS One. 2012;7(12):e52154.

Ben-Sahra I, Dirat B, Laurent K, Puissant A, Auberger P, Budanov A, Tanti JF,  Bost F. Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death. Cell Death Differ. 2012 Dec 14.

Bost F, Ben-Sahra I, Tanti JF. Prevention of mutagenesis: new potential mechanisms of metformin action in neoplastic cells. Cancer Prev Res (Phila). 2012 Apr;5(4):503-6.

Bost F, Sahra IB, Le Marchand-Brustel Y, Tanti JF. Metformin and cancer therapy. Curr Opin Oncol. 2012 Jan;24(1):103-8.


Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011 Jul 1;71(13):4366-72. Epub 2011 May 3..

Plaisant M, Giorgetti-Peraldi S, Gabrielson M, Loubat A, Dani C, Peraldi P. Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells. PLoS One. 2011 Feb 3;6(2).


Jager J, Corcelle V, Grémeaux T, Laurent K, Waget A, Pagès G, Binétruy B, Le Marchand-Brustel Y, Burcelin R, Bost F, Tanti JF : Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity. Diabetologia. 2010 Oct 15

Sahra IB, Tanti JF, Bost F : The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK dependent apoptosis in prostate cancer cells. Autophagy. 2010 Jul 21;6(5)

Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F : Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010 May;9(5):1092-9. Review

Dray C, Debard C, Jager J, Disse E, Daviaud D, Martin P, Attané C, Wanecq E, Guigné C, Bost F, Tanti JF, Laville M, Vidal H, Valet P, Castan-Laurell I : Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1161-9

Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010 Mar 15;70(6):2465-75.

Regazzetti C, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S. Insulin induces REDD1 expression through hypoxia-inducible factor 1 activation in adipocytes. J Biol Chem. 2010 Feb 19;285(8):5157-64.

Jager J, Grémeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF. The Tpl2 kinase is up-regulated in adipose tissue in obesity and may mediate IL-1{beta} and TNF-{alpha} effects on ERK activation and lipolysis.
Diabetes. 2010 Jan;59(1):61-70


Oldani A, Cormont M, Hofman V, Chiozzi V, Oregioni O, Canonici A, Sciullo A, Sommi P, Fabbri A, Ricci V, Boquet P.Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells.
PLoS Pathog. 2009 Oct;5(10):e1000603.

Tanti JF and Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009 Aug 13.

Vincent Kaddai, Teresa Gonzalez, Frédérique Keslair, Thierry Grémeaux, Stéphanie Bonnafous, Jean Gugenheim, Albert Tran, Philippe Gual, Yannick Le Marchand-Brustel and Mireille Cormont.
Rab4b is a small GTPase involved in the control of the glucose transporter GLUT4 localization in adipocyte
PLoS ONE, Avril 2009 ()

Kaddai V, Jager J, Gonzalez T, Najem-Lendom R, Bonnafous S, Tran A, Le Marchand-Brustel Y, Gual P, Tanti JF, Cormont M.
Involvement of TNF-alpha in abnormal adipocyte and muscle sortilin expression in obese mice and humans. Diabetologia. 2009 May;52(5):932-40. Epub 2009 Feb 14.

Poggi M, Jager J, Paulmyer-Lacroix O, Peiretti F, Gremeaux T, Verdier M, Grino M, Stepanian A, Msika S, Burcelin R, de Prost D, Tanti JF, Alessi MC.
The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia. 2009 Jun;52(6):1152-63. Epub 2009 Jan 31.

Regazzetti C, Peraldi P, Grémeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S.
Hypoxia decreases insulin signaling pathways in adipocytes.
Diabetes. 2009 Jan;58(1):95-103. Epub 2008 Nov 4.


Kaddai V, Gonzalez T, Bolla M, Le Marchand-Brustel Y, Cormont M.
The nitric oxide-donating derivative of acetylsalicylic acid, NCX 4016, stimulates glucose transport and glucose transporters translocation in 3T3-L1 adipocytes.
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E162-169.

Kaddai V, Le Marchand-Brustel Y, Cormont M. Rab proteins in endocytosis and Glut4 trafficking. Acta Physiol (Oxf). 2008 Jan;192(1):75-88. Review.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F.
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.
Oncogene. 2008 Jun 5;27(25):3576-86.   


Aouadi M, Jager J, Laurent K, Gonzalez T, Cormont M, Binétruy B, Le Marchand-Brustel Y, Tanti JF, Bost F.
p38MAP Kinase activity is required for human primary adipocyte differentiation.
FEBS Lett. 2007 Dec 11;581(29):5591-6. Epub 2007 Nov 13.

Jager J, Grémeaux T, Cormont M , Le Marchand-Brustel Y, Tanti JF. Interleukin-1b-induced insulin resistance in adipocytes through down-regulation of IRS-1 expression. Endocrinology, 2007; 148: 241-251

Gauthier NC, Monzo P, Gonzalez T, Doye A, Oldani A, Gounon P, Ricci V, Cormont M, Boquet P. Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin. J Cell Biol. 2007; 177: 343-354.


Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binétruy B and Bost F. Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes, 2006; 55: 281-289.

Mari M, Monzo P, Kaddai V, Le Marchand-Brustel Y and Cormont M. The Rab4 effector Rabip4 plays a role in intracellular trafficking of Glut 4 in 3T3-L1 adipocytes. J Cell Sci, 2006;117: 1297-1306.

Vukmirica J, Monzo P, Le Marchand-Brustel Y, Cormont M. The Rab4a effector protein Rabip4 is involved in migration of NIH 3T3 fibroblasts. J Biol Chem, 2006; 281: 36360-3 6368

Barrès R, Grémeaux T, Gual P, Gonzalez T, Gugenheim j, Tran A, Le Marchand-Brustel Y, Tanti JF. Enigma interacts with APS to control insulin-induced actin cytoskeleton remodeling and glut4 translocation. Mol Endocrinol., 2006 Nov;20(11):2864-75.


Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pages G, Pouyssegur J, Le Marchand-Brustel Y and Binetruy B. The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes, 2005; 54:402-411.

Monzo P, Gauthier NC, Keslair F, Loubat A, Field CM, Le Marchand-Brustel Y and Cormont M. Clues to CD2-associated protein involvement in cytokinesis. Mol Biol Cell, 2005; 16:2891-2902.


Cormont M, Meton I, Mari M, Monzo P, Keslair F, Gaskin C, McGraw TE and Le Marchand-Brustel Y. CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl.Traffic, 2003; 4:97-112.

Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF and Vidal H. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes, 2003; 52:1319-1325.

Gual P, Grémeaux T, Gonzalez T, Le Marchand-Brustel Y and Tanti JF. MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632. Diabetologia, 2003; 46:1532-1542.

Gual P, Gonzalez T, Grémeaux T, Barres R, Le Marchand-Brustel Y and Tanti JF. Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes. J Biol Chem, 2003; 278:26550-26557.

Bost F, Caron L, Marchetti I, Dani C, Le Marchand-Brustel Y and Binetruy B. Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. Biochem J, 2002; 361:621-627.

Cormont M, Mari M, Galmiche A, Hofman P and Le Marchand-Brustel Y. A FYVE-finger-containing protein, Rabip4, is a Rab4 effector involved in early endosomal traffic. Proc Natl Acad Sci USA, 2001; 98:1637-1642.

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