Lipid sensing along the oro-intestinal tract: impact on eating behavior and obesity risk Obesity reaches epidemic levels in the world. By reason of deleterious effects of obesity-associated diseases (i.e. type 2 diabetes, vascular disorders, hypertension, cancer), it is one of the major public health challenges of the 21rd century. During the past 20 years, its prevalence has tripled in many countries and the number of people affected continues to rise at an alarming rate, especially among children. Chronic overconsumption of foods high in fat, coupled with a quantitative imbalance (i.e. excess saturated fat, cholesterol, high ratio omega6/omega3) has been identified as one of key factors of this epidemic. It was reported that laboratory rodents and humans display a spontaneous preference for fat through poorly known mechanisms. We have recently brought the first demonstration that a lipid-binding proteins (i.e. CD36) found both in the taste buds and gut, acts as a lipid-sensor implicated in the selection, digestion and absorption of fat-rich foods (ANR PRNA SensoFAT, 2008-2010). By promoting the efficiency of energy storage by the body, the original sensing system might constitute an evolutionary advantage to survive to periods of food scarcity. Conversely, it might be a risk factor for obesity in the case of continuous food abundance. Nevertheless, this lipid-sensing system is more complex than previously expected since G protein-coupled receptors (GPCR) might also play the role of lipid-sensors along the oro-intestinal tract. Moreover, lipid sensing in oral cavity and intestinal lumen seems to be hormone-sensitive. Finally, our growing knowledge about the pleiotropic actions of gut microbiota, which the diversity is modulated by dietary lipids, raises the question of its involvement in the regulation of oro-intestinal lipid sensing system. The goal of the SensoFAT2 project is to further explore the mechanism of detection of dietary fat along the oro-intestinal axis by attempting to answer the following questions: What is (are) the respective role(s) of lipid-receptors found both in taste buds and small intestine? What are the cellular and molecular mechanisms involved? How are they regulated? Do nutritional, hormonal, microbiotal environment affect their function(s)? Performed using various original mouse models, this investigation will be complementary to a clinical human trial (i.e. HumanFATaste program*) performed simultaneously in Dijon. Altogether data from these animal and human studies should lead to novel nutritional strategies and/or alternative pharmacological treatments in order to limit the consumption of foods high in fat and obesity risk. (*) Funding (2010-2012): Centre National Inter-professionnel de l’Economie Laitière – CNIEL and Burgundy Council. Coordination: Pr P. Besnard U 866.

The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central nervous system (CNS) is an intricate and fragile structure which on one hand open to change The mammalian central ner

Many neurological diseases may benefit from replacement of glial cells (e.g. Multiple Sclerosis, Leukomalacia) or neurons (e.g. Parkinson, Alzheimer) or both (stroke). Replacement could be achieved by stimulating neural stem cells (NSC) to favour endogenous repair. Yet our understanding of how neurons and glial cells are generated during development and in the adult is still insufficient to move forward to therapeutic goals. The molecular mechanisms underlying the glial versus neuronal early fate choice of progenitors are largely unknown, particularly in the mature brain. Thyroid hormone (TH) is a key inductor of neurogenesis as well as myelin synthesis by oligodendrocytes. It is therefore unclear how TH can orient cell fate decision towards one or the other direction. Taking advantage of newly developed in vivo experimental approaches, we have acquired better knowledge of the adult NSC niche and data highlighting the roles of TH in orienting NSC towards a neuronal or oligodendroglial fate. Without bringing into question the large body of data on TH enhancement of (re)myelination in many models, we have obtained novel data on early stages of oligodendrocyte determination. A solid series of unpublished results shows that, at the early progenitor level, oligodendrocyte determination in the adult brain actually requires a transient TH -free environment. Since endogenous repair of neurodegenerative (e.g. Parkinson, Alzheimer) or neuroinflammatory disease (Multiple Sclerosis) would require preferentially neurogenesis or oligodendrogenesis from NSC, respectively, the aim of our project is to decipher the molecular mechanisms by which TH orient the glial versus neuronal fate. As neuronal versus glial decisions during embryonic, post-embryonic and maturity are strongly spatially and temporally defined, we will address the question of how TH modulates these decisions using two distinct stages, adult neurogenesis and the perinatal period in mammals, with its parallel of pre-metamorphosis in amphibians. To this end, we will take advantage of state of the evolutionary conservation of TH signalling to address how TH modulates neuronal versus glial decisions in two classes of vertebrates: in the murine Subventricular Zone and in the optic nerve of pre-metamorphic Xenopus tadpoles. The results of our study will bring in depth knowledge of the links between TH availability, adult NSC functions and the programs regulating NSC fate decisions within the complex architecture of neurogenic regions. They could have significant consequences in understanding repair processes when proposing treatments for neurological diseases, notably Multiple Sclerosis. We will take advantage of state of the art techniques mastered in the participating laboratories to determine: 1) The cellular effects of TH availability on stem and progenitor cell biology (P1 P2) 2) The effects of T3 on specific cell populations (P1 P2) 3) Interactions between EGFR signalling and TH pathways on progenitor cell commitment (P1). 4) The consequences of demyelination on progenitor responses /commitment (P1 P2) To understand genetic regulations induced by TH in these cell fate decisions we will use transcriptomic approaches to determine genetic networks and nodes underlying TH action in defined cell populations e.g. FACS-isolated adult oligodendrocyte precursor cells (OPCs) or newly generated OPCs isolated from mice in hypothyroid states at the time of demyelination. TH-target genes so identified, that represent key nodes implicated in determining cell fate responses, will provide candidates for potential therapeutic targets. Results could have significant consequences in understanding repair processes when proposing treatments for pathologies (Multiple Sclerosis), where new oligodendrocytes capable of remyelination are needed. In contrast, in the case of stroke or certain neurodegenerative diseases, it may be of interest to generate in one step both neurons and glia, or just neurons.