Group leader : Mohammed Taouis
Our team studies the mechanisms involved in the onset of the hypothalamic leptin/insulin resistance. Our objective is to understand how inappropriate endocrine and metabolic environments during early life durably impair hypothalamic neuronal organization and leptin/insulin signaling.
In line with our previous findings we will continue our focus on two main objectives :
1/ deciphering molecular mechanisms involved in neural insulin/leptin resistance in hypothalamic nuclei to respond to the question : by which mechanisms insulin/leptin hypothalamic resistance promotes obesity, type 2 diabetes and behavioural dysfunctions (concerning the control of food intake) ;
2/ identify the main miRNAs implicated in metabolic programming and validate their targets in hypothalamic nuclei.
To achieve these objectives, we will combine several approaches from molecular to more integrated techniques using cellular and animal models.
1. Molecular and cellular mechanisms involved in hypothalamic insulin and leptin resistance
As previously described, hypothalamic leptin sensitivity is critical in the control of energy homeostasis and neuronal organization. Previously, we have demonstrated that leptin, insulin, CNTF and serotonin share common signaling pathways. We have showed that both leptin and insulin resistances are associated, linking then obesity to type 2 diabetes through most likely resistin. This part of our project will be organized in the following tasks.
Cellular and molecular mechanisms of resistin/TLR4-dependent hypothalamic nuclei inflammation and insulin resistance
Resistin induces hypothalamic neuro-inflammation (Benomar et al., 2013)
2. Impact of hypothalamic hormonal and metabolic environment during perinatal periods
* Expression profile of hypothalamic microRNA :
According to our previous studies we hypothesize that changes of specific miRNA expression levels may be involved, at least partially, in the process of diet or hormonal induced alteration of hypothalamic neuronal organization during early life. Furthermore, we will continue the improvement this technique by developing a guideline to quantify barcoding impact in multiplex microRNA expression profiles using Illumina technology.
Validation and the physiological relevance of miRNAs.
The characterization of specific miRNAs will be validated by in situ hybridization (ISH) to specifically confirm their localization in specific hypothalamic nuclei.
Validation and the physiological relevance of hypothalamic miRNAs