Neurons of the arcuate nucleus of the hypothalamus (ARH) are a key center of metabolic regulation. Thus, molecular communications between the brain and the periphery are absolutely necessary to regulate physiological functions such as the regulation of body weight and glucose homeostasis. However, the exact molecular mechanisms underlying the entry of hormones into the brain are not known, nor the impact of altered entry. One of those key circulating molecules requiring entry into ARH to regulate metabolic function is leptin, an appetite suppressing hormone that regulates satiety. The passage of molecules to the ARH is tightly regulated by two distinct barriers, positioned dorsally and laterally, which prevent the free diffusion of molecules between the brain and the periphery. Our team, in collaboration with Vincent Prévot's team (INSERM UMR-S 1172, Lille), recently demonstrated the mechanisms of leptin transport in the hypothalamus through the dorsal barrier, formed by the tanycytic cells of the median eminence. We have shown that the entry of leptin into the brain involves the molecular complex between the leptin receptor and the EGF receptor and we have demonstrated the consequences of an alteration of leptin transport in obesity and type 2 diabetes. (;

The objective of the current project is to investigate the involvement of other important receptors expressed in the tanycytic barrier and whose function there is not known. The project also aims to determine the physio-pathological role of the as yet unexplored 'lateral diffusion barrier' in the dialogue between the brain and the periphery. We will be working to decipher the mechanisms by which these barriers are regulated by metabolic receptors, and to assess the extent to which they are altered in the development of metabolic disorders.

These projects are being conducted in collaboration with the teams of Dr Virginie Mattot (INSERM UMR-S 1172, Lille), of Dr Stéphane Gasman (INCI, CNRS UPR3212, Strasbourg), and of Dr Ines Martinez-Corral (INSERM UMR-S 1172, Lille).