Abstract

Introduction: Hypothalamic tanycytes are involved in the brain glucose-sensing mechanism, a process based on a metabolic coupling with neurons of the arcuate nucleus (ARC) that regulate food intake. Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, and GKRP, the unique endogenous inhibitor of GK, are expressed in tanycytes. Here, we evaluate if tanycyte GKRP expression modulate the GK-dependent anorexigenic signals derived by tanycytes over neurons. Materials and methods: We generated four adenoviruses expressing GKRP (GKRP-Venus), GKRP shRNA (shGKRP-EGFP), and their respective controls. We used RT-qPCR to analyze orexigenic and anorexigenic neuropeptide expression in rats, in response to i.c.v. glucose injections after inhibition or overexpression of GKRP. Finally, we evaluated the effects of gain and loss of GKRP expression over feeding behavior, in response to fasting-refeeding cycles, using a computational system coupled to feeding cages. Results: In vivo knock-down of GKRP expression alters neuropeptides expression profile in response to increased glucose concentration compared to control group. Also, this group showed a significant decrease on food intake and body weight, increasing the duration of the inter-meal intervals. Conversely, overexpression of GKRP in tanycytes, produces high levels of orexigenic neuropeptides in fasting conditions, showing an increase in first meal duration respect to control group. Discussion: Gain or loss of GKRP expression in tanycytes showed alterations in the expression profile of neuropeptides in response to glucose and changes in the normal feeding behavior. Our data suggest that GKRP play a critical role as an endogenous inhibitor of satiety signals production in tanycytes. Acknowledgements: FONDECYT 1180871