The endocannabinoid system (ECS) is composed of a group of Gi-coupled protein receptors and enzymes, producing and degrading the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA). Endocannabinoid-mediated signaling modulates brain functions, such as pain, mood, memory, and feeding behavior. The activation of the ECS is associated with overeating and obesity; however, the expression of components of this system has been only partially studied in the hypothalamus, a critical region implicated in feeding behavior. Within this brain region, anorexigenic, and orexigenic neurons of the arcuate nucleus (ARC) are in close contact with tanycytes, glial radial-like cells that line the lateral walls and floor of the third ventricle (3V). The specific function of tanycytes and the effects of metabolic signals generated by them on adjacent neurons is starting to be elucidated. We have proposed that the ECS within tanycytes modulates ARC neurons, thus modifying food intake. Here, we evaluated the expression and the loss of function of the 2-AG-producing enzyme, diacylglycerol lipase-alpha (DAGLα). Using Western blot and immunohistochemistry analyses in basal hypothalamus sections of adult rats under several glycemic conditions, we confirm that DAGLα is strongly expressed at the basal hypothalamus in glial and neuronal cells, increasing further in response to greater extracellular glucose levels. Using a DAGLα-inhibiting adenovirus (shRNA), suppression of DAGLα expression in tanycytes altered the usual response to intracerebroventricular glucose in terms of neuropeptides produced by neurons of the ARC. Thus, these results strongly suggest that the tanycytes could generate 2-AG, which modulates the function of anorexigenic and orexigenic neurons.
Objectives : Glucokinase Regulatory Protein (GKRP) is the only known endogenous modulator of glucokinase (GK) localization and activity to date, and both proteins are localized in tanycytes, radial glia-like cells involved in metabolic and endocrine functions in the hypothalamus. However, the role of tanycytic GKRP and its impact on the regulation of feeding behavior has not been investigated. Here, we hypothesize that GKRP regulates feeding behavior by modulating tanycyte-neuron metabolic communication in the arcuate nucleus. Methods : We used primary cultures of tanycytes to evaluate the production of lactate and β-hydroxybutyrate (βHB). Similarly, we examined the electrophysiological responses to these metabolites in pro-opiomelanocortin (POMC) neurons in hypothalamic slices. To evaluate the role of GKRP in feeding behavior, we generated tanycyte-selective GKRP-overexpressing and GKRP-knock down mice (GKRP t -OE and GKRP t -KD respectively) using adenovirus-mediated transduction. Results : We demonstrated that lactate release induced by glucose uptake is favored in GKRP-KD tanycytes. Conversely, tanycytes overexpressing GKRP showed an increase in βHB efflux induced by low glucose concentration. In line with these findings, the excitability of POMC neurons was enhanced by lactate and decreased in the presence of βHB. In GKRP t -OE rats, we found an increase in post-fasting food avidity, whereas GKRP t -KD caused a significant decrease in feeding and body weight, which is reverted when MCT1 is silenced. Conclusion : Our study highlights the role of tanycytic GKRP in metabolic regulation and positions this regulator of GK as a therapeutic target for boosting satiety in patients with obesity problems.
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