Obesity and its metabolic consequences (type-2 diabetes, cardiovascular, gastrointestinal and reproductive disorders, as well as certain cancers) have become major causes of morbidity and mortality in developed countries. In France today, 50% of adults (22 million) are overweight, of which 7 million are obese, and the past 30 years have witnessed an alarming 7-fold increase in the incidence of childhood obesity. The development of effective preventive and therapeutic measures for these disorders and the reduction of the associated medical, familial and socioeconomic burdens is impossible without an improved understanding of the pathways and mechanisms leading to obesity. Among these mechanisms is the transport of peripheral metabolic hormones into the brain, a critical limiting step whose deregulation leads to these disorders. Current evidence indicates that the brain is a key site processing information from “adiposity signals” such as the anorexigenic hormone leptin, which circulates in proportion to body fat mass and instructs the individual to stop feeding. Leptin receptors are expressed in regions of the hypothalamus involved in the control of food intake and energy homeostasis, and injections of leptin into the brain of leptin-deficient mice eliminate overfeeding. Conversely, the deletion of leptin receptors or the blockade of leptin entry into the brain results in obesity and resistance to this hormone. During previous work supported by the ANR (GLIODIABESITY, 2009-2013), we raised the groundbreaking notion that tanycytes, a specific type of hypothalamic glial cells, act as “gatekeepers” that regulate the access of blood-borne signals to the hypothalamus (Langlet et al., Cell Metab 2013), and in particular, its vesicular transport into the cerebrospinal fluid, from where it enters other leptin-sensitive regions (Balland et al., Cell Metab 2014). We have shown that this tanycyte-mediated transport of leptin is suppressed in both genetic and diet-induced obesity (Balland et al., Cell Metab 2014). Reversing leptin resistance by restoring tanycytic leptin transport holds important therapeutic potential (Patent WO 2014141124 A1, PI: Prevot V), as shown by previous positive reviews by the ANR, as well as two Marie Sklodowska Curie postdoctoral fellowships in 2015 to pursue this work. However, the molecular mechanisms involved in the tanycytic shuttling of blood-borne leptin into the hypothalamus are still largely unknown. The overall objective of this proposal is to further develop this highly original angle by developing state-of-the-art approaches to i) characterize leptin transporters and the trans-tanycytic route used by peripheral leptin to enter the metabolic brain (Aims 1 and 2), ii) assess whether endoplasmic reticulum stress, which is involved in leptin resistance, alters tanycytic leptin transport (Aim 3), and iii) develop novel models and cutting-edge tools to probe this tanycytic barrier in vitro (Aim 4). To carry out this innovative project in a highly competitive field of biomedical research, we are now teaming up with a group of internationally renowned experts in leptin signaling who have contributed to the aforementioned discoveries (Partner 2: Ralf Jockers & Julie Dam), and a second partner expert in intracellular vesicular trafficking (Partner 3: Stéphane Gasman). We are convinced that the successful outcome of the proposed research plan will have important implications for public health by providing essential clues about how the peripheral hormone leptin, which carries metabolic information to the CNS both during development and adulthood, enters the brain. More broadly, this research promises to shed new light on the cellular and molecular mechanisms used by the hypothalamus to integrate endocrine signals that coordinate energy homeostasis. The results will pave the way for the development of new treatment strategies to overcome hormone resistance in human obesity and associated metabolic syndromes.