Descripción del proyecto
Una nueva era para el desarrollo de fármacos contra la obesidad
La obesidad, una crisis de salud pública en aumento, va acompañada de un incremento alarmante de dolencias crónicas como la diabetes, las enfermedades cardiovasculares y el cáncer. El intrincado control del balance energético, dirigido por el núcleo arqueado del hipotálamo, desempeña un papel fundamental. Sin embargo, a pesar de nuestro conocimiento de esta regulación central, se nos han escapado tratamientos eficaces. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto FEEDING pretende comprender mejor esta complejidad aventurándose en el territorio inexplorado de los receptores huérfanos de la familia de receptores acoplados a la proteína G y su interacción con los receptores de leptina. Mediante el ingenioso empleo de modelos de inactivación, agentes farmacológicos y evaluaciones metabólicas, los científicos tratan de descifrar el código de la resistencia a la leptina. Esta iniciativa puede redefinir la lucha contra la obesidad.
Objetivo
"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."
Ámbito científico
- 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
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
4000 Liege
Bélgica