GLIODIABESITY · ROLE OF THE TANYCYTIC BARRIER AT THE BLOOD-HYPOTHALAMUS INTERFACE DURING METABOLIC DISORDER DEVELOPMENT

ROLE OF THE TANYCYTIC BARRIER AT THE BLOOD-HYPOTHALAMUS INTERFACE DURING METABOLIC DISORDER DEVELOPMENT

Metabolic disorders such as obesity and diabetes are age-related diseases, and lead cause of death in Europe. Adiposity signals such as leptin and insulin, whose circulating levels are in proportion to body fat, convey metabolic information to neural networks that regulate energy homeostasis in the hypothalamus. In leptin-deficient humans and mice, leptin administration effectively reduces hyperphagia and obesity. Paradoxically, most cases of obesity display high circulating leptin levels that fail to reduce appetite or increase energy expenditure. This raises the possibility that leptin-receptor-expressing neuronal and/or non-neuronal cells in the hypothalamus either cannot access circulating leptin or are deficient in leptin binding. To reach the arcuate nucleus of the hypothalamus (ARH), leptin must cross the blood-brain barrier at the level of the median eminence (ME) of the hypothalamus. The host laboratory has characterized a particular type of blood-brain barrier in the ME, revealing that tanycytes, a specialized class of glia lining the floor of the third ventricle (3v), possess properties of barrier cells and that they were responsible for shuttling leptin from the periphery and that such conduit was blunted in mice with diet-induced obesity. Thus, leptin transport by tanycytes could play a critical role in the pathophysiology of leptin resistance. Nonetheless, how substances taken up by tanycytes are transported along their processes from their basal end-feet to their apical pole for delivery into the 3v, as well as the molecular mechanisms by what they are secreted for transmission remain unknown. This project aims to elucidate whether the alteration of the adiposity signals transport into the metabolic brain across hypothalamic barriers is the main cause of the onset of obesity, as well as to characterize the transtanycytic route taken by these signals to reach the ARH to regulate energy homeostasis. In addition, we aimed to define the role of microRNAs in this transport. To this end, a combination of in vitro and in vivo approaches, using genetically modified mice and pre-clinical models of obesity, were used. The implementation of this project will expand our knowledge of the mechanism underlying human obesity and hold therapeutic potential for treating it.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз