Description du projet
Une nouvelle ère dans le développement de médicaments contre l’obésité
L’obésité, une crise de santé publique de plus en plus grave, s’accompagne d’une augmentation alarmante des maladies chroniques telles que le diabète, les troubles cardiovasculaires et le cancer. Le contrôle complexe de l’équilibre énergétique, dirigé par le noyau arqué de l’hypothalamus, joue un rôle essentiel. Pourtant, malgré notre connaissance de cette régulation centrale, nous ne disposons pas de traitements efficaces. Avec le soutien du programme Actions Marie Skłodowska-Curie, le projet FEEDING vise à mieux comprendre cette complexité en s’aventurant sur le territoire inexploré des récepteurs orphelins couplés aux protéines G et de leur interaction avec les récepteurs de la leptine. Grâce à l’utilisation ingénieuse de modèles d’invalidation génétique (ou modèles «knock-out»), d’agents pharmacologiques et d’évaluations métaboliques, les scientifiques chercheront à déchiffrer le code de la résistance à la leptine. Cette initiative pourrait révolutionner la lutte contre l’obésité.
Objectif
"Obesity is a major burden to public health as it increases the risk of several chronic diseases, like diabetes, cardiovascular diseases, musculoskeletal disorders or some cancers. Energy homeostasis is centrally regulated by the hypothalamus where the arcuate nucleus (ARC) orchestrates feeding behaviors and energy balance. Two neuronal populations of the ARC are considered as the first-order neurons mediating the effects of various signals such as leptin and insulin, the orexigenic neuropeptide (NP)Y/Agouti-related peptide (AgRP) neurons and the anorexigenic pro-opiomelanocortin (POMC)/Amphetamine-regulated transcript (CART) neurons. Leptin is an adipocyte-secreted peptidic hormone that inhibits food intake and regulates body weight. Nearly in all forms of obesity, circulating levels of leptin increase but fail to suppress food intake and body weight. This condition has been identified as ""leptin resistance"".
G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and a notoriously successful source of drug targets. However, many GPCRs are understudied or even orphans meaning they have no known ligands. Despite our knowledge of the principal circuits regulating feeding, satiety, hunger and energy expenditure, we have been unable to deliver effective drugs targeting these systems. The failure in targeting the melanocortin pathways comes out partly from an incomplete understanding of leptin action, especially leptin resistance, at the central level. Here, we propose to investigate the interplay between the signaling of orphan GPCR and leptin receptor in leptin sensitive cells of the arcuate nucleus. To do so, we will use conditional knockout animals and pharmacological modulators. We will measure various metabolic parameters including weight and food intake with the Comprehensive Laboratory Animal Monitoring System (CLAMS). We will also establish hypothalamic cell cultures in which we will address the impact of G protein signaling on leptin."
Champ scientifique
- medical and health scienceshealth sciencespublic health
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- medical and health sciencesbasic medicinephysiologyhomeostasis
- medical and health scienceshealth sciencesnutritionobesity
Mots‑clés
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
4000 Liege
Belgique