Supervisors : Etienne Challet & Andries Kalsbeek
Energy metabolism and food intake are regulated in the brain by a network of nuclei in the mediobasal hypothalamus (i.e., PVN, DMH, VMH, ARC) and brainstem (i.e., NTS and PB). Several neuropeptides have opposite actions on food intake and energy expenditure: NPY, AgRP and orexin (hypocretin) are orexigenic and energy-sparing effects while CART and aMSH are anorexigenic and stimulate energy expenditure. All brain structures linked to energy metabolism and listed above contain a putative clockwork. The circadian clockwork relies on feedback loops involving a set of clock genes such as Per1, Per2 and some nuclear receptors (e.g., Rev-erba and Rora). REV-ERBa plays a pivotal role in the circadian control of energy metabolism. In addition to its participation to the clockwork, it has been implicated in various peripheral metabolic pathways (e.g., metabolism of cholesterol and bile acid, as well as adipocyte differentiation)
In the Strasbourg part of the project, the candidate will study Rev-erba KO mice. These mice show mild hyperglycemia when fed with chow or high-fat diet, and even after food deprivation, suggesting impaired regulation by the brain. To test this hypothesis, we will investigate glucose production, glucose sensing and hypoglycemic counter-regulation in mice germline knock-out for Rev-erba in comparison with mice bearing a genetic ablation of Rev-erba only in the brain. We will also establish the daily patterns of hypothalamic and brainstem neuropeptides in these mice challenged with various nutritional conditions to get an integrated view of the impact of brain clockwork on the daily regulation of food intake and energy metabolism.
In the Amsterdam part of the project, the candidate will use rats to study the role of Rev-erba, with a focus on the brain and the liver. The daily rhythm of Rev-erba expression will be studied in rats on different diets, as well as in animals that are forced to eat their diet or specific components of the diet during specific parts of the light/dark-cycle. In addition to these correlative experiments we will use hypothalamic micro-injections with a specific Rev-erba agonist to obtain functional data on the significance of Rev-erba in the central control of energy metabolism.
The molecular clock mechanism