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. (PMID: 24506870; PMID: 34341568). However, no data is available on the other so-called "lateral" barrier blocking the entry of circulating molecules into the brain.

The current project therefore aims to determine the physio-pathological role of the still unexplored “lateral diffusion barrier” in the dialogue between the brain and the periphery. We will endeavor to decipher the mechanisms of regulation of this barrier by metabolic receptors, and to evaluate its alteration in the appearance of metabolic disorders.

This study is carried out in collaboration with the teams of Virginie Mattot (INSERM UMR-S 1172, Lille) and Stéphane Gasman (INCI, CNRS UPR3212, Strasbourg)

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