Project

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Investigating the role of PI3Kgamma in obesity-related diseases

English title Investigating the role of PI3Kgamma in obesity-related diseases
Applicant Solinas Giovanni
Number 135684
Funding scheme Project funding
Research institution Division de Physiologie Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Physiology : other topics
Start/End 01.05.2011 - 30.04.2014
Approved amount 250'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Endocrinology

Keywords (5)

Obesity; Inflammation; Insulin Resistance; PI3K?; NASH

Lay Summary (English)

Lead
Lay summary
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The worldepidemic of obesity is a major contributor to the global burden of severalchronic diseases. Research aimed to understand the metabolic stress associatedwith obesity suggests that inflammation is an important pathogenic factor inobesity-induced glucose intolerance. Our previous studies suggested a majorrole for the pro-inflammatory kinase PI3Kgamma in diet-induced obesity,obesity-induced inflammation, fatty liver, and insulin resistance. We have alsoshown that PI3Kgamma role in obesity and obesity-mediated stress islargely consequent to its action in promoting metabolic efficiency for fat massgain, a mechanism operating in a cell-type o non-hematopoietic origin.

            Inthis project we aim to identify the precise cell type where PI3Kgamma promotes positive energy balance,and thereby diet-induced obesity and insulin resistance. This objective will setthe ground to identify the precise molecular mechanism of action of PI3Kgamma in diet-induced obesity, insulinresistance and fatty liver.

             Overallwe expect that this project will lead to a significant advancement of ourunderstanding of the role of PI3Kgamma in the pathogenesis ofobesity-related diseases, and in particular insulin resistance and nonalcoholic fatty liver diseases.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
JNK at the crossroad of obesity, insulin resistance, and cell stress response
Solinas Giovanni, Becattini Barbara (2016), JNK at the crossroad of obesity, insulin resistance, and cell stress response, in Molecular Metabolism, 1-11.
JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage
Becattini B., Zani F., Breasson L., Sardi C., D'Agostino V. G., Choo M.-K., Provenzani A., Park J. M., Solinas G. (2016), JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage, in The FASEB Journal, 30(9), 3124-3132.
A Role for Adipose Tissue De Novo Lipogenesis in Glucose Homeostasis During Catch-up Growth
Marcelino Helena, Veyrat-Durebex Christelle, Summermatter Serge, Sarafian Delphine, Miles-Chan Jennifer, Arsenijevic Denis, Zani F, Montani Jean-Pierre, Seydoux Josiane, Solinas Giovanni, Rohner-Jeanrenaud Françoise, Dulloo Abdul (2013), A Role for Adipose Tissue De Novo Lipogenesis in Glucose Homeostasis During Catch-up Growth, in Diabetes, 62((2) Februa), 362-372.
Inhibition of phosphoinositide 3-kinase gamma attenuates inflammation, obesity, and cardiovascular risk factors
Wymann Matthias, Solinas Giovanni (2013), Inhibition of phosphoinositide 3-kinase gamma attenuates inflammation, obesity, and cardiovascular risk factors, in Ann N Y Acad Sci., 1280 (March (201), 44-47.
PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and GL expression
Zani Fabio, Breasson Ludovic, Becattini Barbara, Vukolic Ana, Montani Jean-Pierre, Albrecht Urs, Provenzani Alessandro, Ripperger Juergen A., Solinas Giovanni (2013), PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and GL expression, in Molecular Metabolism, 292-305.
Molecular pathways linking metabolic inflammation and thermogenesis.
Solinas Giovanni (2012), Molecular pathways linking metabolic inflammation and thermogenesis., in Obesity Reviews, 13(S2), 69-82.
PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance.
Becattini Barbara, Marone Romina, Zani Fabio, Arsenijevic Denis, Seydoux Josiane, Montani Jean-Pierre, Dulloo Abdul G, Thorens Bernard, Preitner Frédéric, Wymann Matthias P, Solinas Giovanni (2011), PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance., in Proceedings of the National Academy of Sciences of the United States of America, 108(42), 854-863.

Collaboration

Group / person Country
Types of collaboration
University of California, San Diego United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Helmholtz Diabetes Conference Talk given at a conference International Diabetes Conference 22.09.2013 Munich, Germany Solinas Giovanni;
20th anniversary of EFSD/Lilly Grant & Fellowship Program Research Symposium Talk given at a conference 20th anniversary of EFSD/Lilly Grant & Fellowship Program Research Symposium 02.05.2013 Bad Homburg Germany , Germany Solinas Giovanni;
Novel Concept in Immunopathology Talk given at a conference Symposia 04.02.2013 Bern, Switzerland Solinas Giovanni;
Helmholtz Diabetes and Obesity Seminars Talk given at a conference Helmholtz Diabetes and Obesity Seminars 16.10.2012 Munich, Germany Solinas Giovanni;
International Society of Nephrology Forefront Symposia Talk given at a conference International Society of Nephrology Forefront Symposia 04.10.2012 Melbourne, Australia Solinas Giovanni;
The EuroMEMBRANE International Conference 2012 Talk given at a conference The EuroMEMBRANE International Conference 2012 05.06.2012 Basel Switzerland, Switzerland Wymann Matthias;
Fribourg Obesity Research Conference (September 23rd 2011 Fribourg Switzerland) Talk given at a conference Fribourg Obesity Research Conference 23.09.2011 Fribourg, Switzerland, Switzerland Solinas Giovanni;


Awards

Title Year
European Foundation for the Study of Diabetes -EFSD- Diabetes and Cancer research Award Grant. 2013
Prix de la Fondation Endocrinologie Geneve 2012

Associated projects

Number Title Start Funding scheme
152998 Investigating the Role of PI3Kgamma in Obesity and Insulin Resistance 01.05.2014 Project funding
118172 Functional study of the role of JNK in obesity and insulin resistance 01.02.2008 Project funding

Abstract

The world epidemic of obesity is a major contributor to the global burden of several chronic diseases. Some diseases associated with obesity occur at a relatively early stage, such as insulin resistance and fatty liver, whereas others are associated with a longer exposure to obesity. Diseases associated with a chronic exposure to obesity include diabetes, non-alcoholic steato-hepatitis (NASH), liver fibrosis, cardiovascular diseases, and kidney dysfunctions. Most likely, the explosive raise of obesity among children will lead within the next decades to a proportional increase of the diseases associated with long-term exposure to obesity. Research aimed to understand the metabolic stress associated with obesity suggests that inflammation is an important pathogenic factor in obesity-induced glucose intolerance. Furthermore, the kinases IKKß and JNK1 were identified to be important molecular links between obesity, inflammation, and insulin resistance. Although several evidences indicate that specific anti-inflammatory interventions may be beneficial for the “early” metabolic derangements associated with obesity (eg. insulin resistance and fatty liver) it is not clear whether an anti-inflammatory therapy would be protective or safe over a longer period or at a more advanced stage of obesity related diseases (e.g. NASH). In this proposal we describe data suggesting a major role for the kinase PI3K? in diet-induced obesity, fatty liver, and insulin resistance. In this project we describe three studies: in the first one we propose to generate mice bearing a tissue-specific mutation at the PI3K? gene to specifically investigate the mechanism of PI3K? in diet-induced obesity, insulin resistance and fatty liver. The second study is aimed at investigating the role of PI3K? in a model of overt steatohepatitis and fibrosis. The aim of the third study is to explore the role the kinase PI3K? in the metabolic stress caused by prolonged exposure to high-fat obesogenic diet and in the associated metabolic dysfunctions. Overall we expect that the experiments here described will lead to a significant advancement of our understanding of the role of PI3K? in the pathogenesis of obesity-related diseases, and in particular insulin resistance and non alcoholic fatty liver disease.
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