The team "Insulin Resistance in Obesity and Type 2 Diabetes" aims to identify cellular and molecular mechanisms that link the pathological remodelling and dysfunction of adipose tissue in obesity to the development of insulin resistance, a central metabolic abnormality in the pathogenesis of type 2 diabetes and metabolic syndrome. By combining multidisciplinary approaches, our research is organized in three highly integrated core programs: 1) the identification of how metabolic stresses contribute to adipose tissue dysfunction and insulin resistance; 2) the study of the impact of altered endosomal trafficking on metabolic dysfunction and insulin resistance in adipose tissue and the liver; and 3) the identification of novel signalling pathways which could mitigate the pathological expansion of adipose tissue. For this translational research, we combine studies of mouse and human cell models as well as mouse models of these pathologies. In these different models, we study the changes in carbohydrate and lipid metabolism as well as the alterations in insulin action and signalling. We use innovative 3D imaging approaches on adipose tissue to quantify morphological and cellular changes, and in collaboration with mathematicians we establish mathematical models to model adipose tissue expansion under physiological and pathological conditions. Our research has contributed to significant advances in the identification of new mechanisms involved in insulin resistance, allowing us to propose new targets to fight insulin resistance and decrease the risk of developing type 2 diabetes.

Projects

People
M. Cormont

M. CormontResearch Director
Mail Mireille.Cormont@univ-cotedazur.fr

People
JF. Tanti

JF. TantiResearch Director
Mail jean-francois.tanti@univ-cotedazur.fr

People
J. Jager

J. JagerResearcher
Mail Jennifer.Jager@univ-cotedazur.fr

People
S. Giorgetti-Peraldi

S. Giorgetti-PeraldiResearcher
Mail sophie.giorgetti-peraldi@univ-cotedazur.fr

Chronic activation of stress-responsive pathways by persistent nutrient overload contributes to the maladaptive responses involved in adipose tissue dysfunction and the development of insulin resistance. Therefore, stress-responsive proteins could be attractive targets against insulin resistance induced by obesity. We have shown that different stress-responsive proteins (p53, REDD1) are induced in adipocytes during obesity, in response to genotoxic stress or hypoxia, and mediate alterations in insulin signalling pathways and in their metabolic and secretory functions (Vergoni B et al, Diabetes 2016, Regazzetti C et al, PLoS One 2012). The objective of this project is to improve our knowledge of the connection between the activation of these stress-responsive proteins and adipose tissue dysfunction and insulin resistance. We are deciphering their mode of action and mechanisms of activation in adipocytes and adipose macrophages, and we are evaluating whether their inhibition can prevent obesity and insulin resistance.  

People
I. Mucel

I. MucelPhD student
Mail ines.mucel@etu.univ-cotedazur.fr

People
R. Clary

R. ClaryPhD student
Mail raphaelle.clary@etu.univ-cotedazur.fr

People
M. Cormont

M. CormontResearch Director
Mail Mireille.Cormont@univ-cotedazur.fr

People
JF. Tanti

JF. TantiResearch Director
Mail jean-francois.tanti@univ-cotedazur.fr

People
J. GILLERON

J. GILLERONResearcher
Mail jerome.gilleron@univ-cotedazur.fr

Our team made the original demonstration that the Rab GTPase Rab4, which is involved in endosomal trafficking, controls glucose transport in adipocytes through the regulation of the translocation of the glucose transporter Glut4 in response to insulin (Cormont et al, Mol Cell Biol 1996; Kaddai et al, PloS One 2009). More recently, we have shown that dysregulation of Rab4b-dependent endocytic trafficking in adipose T cells is a new mechanism involved in adipose tissue dysfunction and insulin resistance development (Gilleron et al, Cell Reports 2018). Also, it was demonstrated that Rab-dependent endocytosis controls liver metabolism (Gilleron J et al, Traffic 2019) and our recent data identify several proteins of the Rab family whose expression in liver is modified depending on the nutritional state. The objective of this project is to improve our knowledge of the role of Rab proteins and their regulators in the control of glucose and lipid metabolism and insulin sensitivity. We are currently exploring if and how Rab proteins tune the metabolism of glucose and lipids and the energetic metabolism in adipocytes, T cells, and hepatocytes. We are also elucidating the role of these novel potential metabolic regulators in the development of insulin resistance.

People
A. Chafik

A. ChafikPhD student
Mail abderrahman.chafik@etu.univ-cotedazur.fr

People
JF. Tanti

JF. TantiResearch Director
Mail jean-francois.tanti@univ-cotedazur.fr

People
M. Cormont

M. CormontResearch Director
Mail Mireille.Cormont@univ-cotedazur.fr

People
JF. Louet

JF. LouetResearcher
Mail Jean-Francois.LOUET@univ-cotedazur.fr

In obesity, the excess calory intake triggers an excessive development of fat mass by promoting hyperplasia and hypertrophy of white adipocytes. Conversely, the mass and activity of thermogenic adipocytes localized in white adipose tissue, called beige or brite adipocytes, is reduced. Stimulating beige adipocyte formation/activity protects against obesity and related metabolic disorders. The objective of this project is to identify new regulators of the beiging adaptation of the white adipose tissue. We are currently studying the central role of transcriptional coactivator in the genetic program controlled by sex hormones during beiging adaptation of white adipose tissue and the functional role of mechanosensitive ion channels in the differentiation and activity of the thermogenic beige adipocytes.

People
B. Angot

B. AngotPhD student
Mail brice.angot@univ-cotedazur.fr

Publications

Focus

Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance.

Authors Gilleron J, Bouget G, Ivanov S, Meziat C, Ceppo F, Vergoni B, Djedaini M, Soprani A, Dumas K, Jacquel A, Yvan-Charvet L, Venteclef N, Tanti JF, Cormont M

Cell reports Dec 2018

DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes.

Authors Vergoni B, Cornejo PJ, Gilleron J, Djedaini M, Ceppo F, Jacquel A, Bouget G, Ginet C, Gonzalez T, Maillet J, Dhennin V, Verbanck M, Auberger P, Froguel P, Tanti JF, Cormont M

Diabetes Oct 2016

Other recent publications

The Stress-Responsive microRNA-34a Alters Insulin Signaling and Actions in Adipocytes through Induction of the Tyrosine Phosphatase PTP1B.

Authors Cornejo PJ, Vergoni B, Ohanna M, Angot B, Gonzalez T, Jager J, Tanti JF, Cormont M

Cells Aug 2022

Unravelling the sex-specific diversity and functions of adrenal gland macrophages.

Authors Dolfi B, Gallerand A, Firulyova MM, Xu Y, Merlin J, Dumont A, Castiglione A, Vaillant N, Quemener S, Gerke H, Stunault MI, Schrank PR, Kim SH, Zhu A, Ding J, Gilleron J, Magnone V, Barbry P, Dombrowicz D, Duranton C, Wakkach A, Blin-Wakkach C, Becher B, Pagnotta S, Argüello RJ, Rantakari P, Chakarov S, Ginhoux F, Zaitsev K, Kim KW, Yvan-Charvet L, Guinamard RR, Williams JW, Ivanov S

Cell reports Jun 2022

Periprostatic adipose tissue displays a chronic hypoxic state that limits its expandability.

Authors Roumiguié M, Estève D, Manceau C, Toulet A, Gilleron J, Belles C, Jia Y, Houël C, Pericart S, LeGonidec S, Valet P, Cormont M, Tanti JF, Malavaud B, Bouloumié A, Milhas D, Muller C

The American journal of pathology Mar 2022

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Patents

Patent Number : Patent Number: PCT/EP2013/072314 International patent number : WO2014064215 TPL2 kinase inhibitors for preventing or treating diabetes and for promoting beta-cell survival

Co-inventors J. Tanti, S Dalle; E Varin; A Wojtusciszyn

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Team activities

  • Organization of the annual AFERO scientific meeting from January 27 to 28, 2022.
  • Welcome to Raphaël Di Vita, a student in M1 of the Master in "Life Sciences" at Université Côte d'Azur, who is doing his internship from February 1 to June 30, 2022 under the supervision of Jerome Gilleron.
  • Participation of the team in the annual congress of the Société Francophone du Diabète which took place in Nice from March 22 to 25, 2022.