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Functional study of the role of JNK in obesity and insulin resistance

English title Functional study of the role of JNK in obesity and insulin resistance
Applicant Solinas Giovanni
Number 118172
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 Endocrinology
Start/End 01.02.2008 - 31.01.2011
Approved amount 270'167.00
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Keywords (8)

obesity; insulin resistance; JNK; Diabetes; NASH; IKKbeta; catch-up growth; Pi3Kgamma, PER2

Lay Summary (English)

Lay summary
Obesity and type-2 diabetes mellitus have reached alarming prevalence. In a widely accepted hypothesis explaining the association between obesity and type-2 diabetes, obesity triggers a chronic low-level inflammation that leads to insulin resistance. The pro-inflammatory kinase JNK is activated during obesity and blockage of JNK by targeted gene mutation protects mice from obesity-induced insulin resistance. JNK is considered as a drug target for the treatment of insulin resistance and type-2 diabetes. Therefore it is very important to understand its mechanism of action and of activation in the pathogenesis of obesity-related diseases and in normal physiology. Our project is focused on two main studies: 1) Test the hypothesis that the negative action of JNK on insulin signaling was selected throughout evolution to play a role in the adaptation to the fasting-refeeding transition. To achieve this goal, we will investigate the effects of acute pharmacological JNK inhibition or targeted jnk1 gene mutation on energy balance and insulin sensitivity in a mouse model of fasting and refeeding driven "catch-up growth". 2) Identify signaling cascades implicated in the activation of JNK in response to the metabolic stress associated to obesity. More specifically we are testing the role of Per2, a component of the circadian clock whose expression is deranged by obesity, and of PI3K?, a proinflammatory kinase that was reported to activate JNK in endothelial cells. PI3K? is activated by the lysophosphatidylcholine receptor, a receptor that was recently implicated in JNK activation in response to lipotoxic stress. Overall these study investigate the possible molecular links between inflammation and catch up growth, and between obesity and insulin resistance. The outcome of these studies will significantly advance our knowledge of the pathogenesis of obesity-induced diseases and may provide new insights for the development of drugs for the treatment of type-2 diabetes and other obesity-induced diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants


Associated projects

Number Title Start Funding scheme
135684 Investigating the role of PI3Kgamma in obesity-related diseases 01.05.2011 Project funding