Highlights d Hypothalamic tanycytes synthesize and secrete Fgf21 under nutritional stress d Palmitate oxidation in tanycytes triggers Fgf21 expression via the ROS/p38-MAPK pathway d Deletion of tanycytic Fgf21 reduces fat depot size and promotes energy expenditure d Deletion of tanycytic Fgf21 promotes lipolysis and browning of WAT

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis. energy homeostasis; monocarboxylate transporters; ␤-hydroxybutyrate; obesity; glucose homeostasis DYSFUNCTION IN BOTH CEREBRAL DETECTION OF NUTRIENTS and integration of circulating signals has been implicated in the pathogenesis of obesity and associated disorders (11). For this reason, numerous studies have explored the possible role of nutrient and endocrine sensing of hypothalamic brain areas and their involvement in energy homeostasis regulation (34). The most studied circulating energy substrate is glucose, which represents a critical nutrient monitored by the brain. As the main energy source for brain cells, glucose also plays an important role in brain energy homeostasis (33). However, evidence showing that the brain can use alternative energy substrates has been provided. For instance, fatty acids and ketone bodies contribute significantly to fulfill brain energy needs under specific conditions (6,13,36). Despite the fact that it has been known for decades that cerebral ketone body utilization increases under particular metabolic conditions (13), central ketone body detection has been poorly studied.Under basal conditions, blood ketone body concentrations are low (Ͻ0.3 mmol/l), and their cerebral utilization is considered to be of little significance. However, ketone body levels are increased under conditions such as fasting, type 1 diabetes, or obesity (13). The brain can use ketone bodies when their blood concentrations reach Ϸ4 mmol/l, a value close to the K m of the monocarboxylate transporter 1 (MCT1) expressed on endothelial cells of cerebral blood vessels for ketone bodies (24,31,44). The brain's ability to use ketone bodies varies from...

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During development, GnRH-1 neurons differentiate extracerebraly from the nasal placode and migrate from the vomeronasal organ to the forebrain along vomeronasal and terminal nerves. Numerous studies have described the influence of different molecules on the migration of GnRH-1 neurons, however, the role of microenvironment cells remains poorly understood. This study used GFAP-GFP transgenic mice to detect glial cells at early developmental stages. Using nasal explant cultures, the comigration of glial cells with GnRH-1 neurons was clearly demonstrated. This in vitro approach showed that glial cells began migrating from the explants before GnRH-1 neurons. They remained ahead of the GnRH-1 migratory front and stopped migrating after the GnRH-1 neurons. The association of these glial cells with the axons combined with gene expression analysis of GFAP-GFP sorted cells enabled them to be identified as olfactory ensheathing cells (OEC). Immunohistochemical analysis revealed the presence of multiple glial cell-type markers showing several OEC subpopulations surrounding GnRH-1 neurons. Moreover, these OEC expressed genes whose products are involved in the migration of GnRH-1 neurons, such as Nelf and Semaphorin 4. In situ data confirmed that the majority of the GnRH-1 neurons were associated with glial cells along the vomeronasal axons in nasal septum and terminal nerves in the nasal forebrain junction as early as E12.5. Overall, these data demonstrate an OEC microenvironment for migrating GnRH-1 neurons during mouse development. The fact that this glial cell type precedes GnRH-1 neurons and encodes for molecules involved in their nasal migration suggests that it participates in the GnRH-1 system ontogenesis.