Abstract
Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1–MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.
Highlights
It has been hypothesized that hypothalamic glucosensing is, at least in part, an indirect process mediated by a metabolic coupling through monocarboxylates between glia and neurons
In order to assess the ability of the adenovirus to inhibit MCT4, different viral titers were tested on the HEK 293T cell line, which showed that 5 × 107 infectious units per mL (IFU/mL) was the most effective and non-toxic titer
Quantification revealed that using AdshMCT4 alone resulted in an 81 ± 3.2% MCT4 inhibition when compared with AdshβGal and 66% MCT4 inhibition using both adenoviruses; a similar significant reduction in MCT1 was obtained in this condition
Summary
It has been hypothesized that hypothalamic glucosensing is, at least in part, an indirect process mediated by a metabolic coupling through monocarboxylates between glia and neurons. Tanycytes, which are hypothalamic radiallike glial cells surrounding the walls of the third ventricle (3V), are potentially key players in energy homeostasis Their position gives them privileged access to the ventricular cerebrospinal fluid (CSF), and their long processes project into the nuclei that control feeding behavior, establishing close contact with anorexigenic and orexigenic neurons of arcuate nucleus (ARC). Mol Neurobiol (2020) 57:896–909 transcript regulated by amphetamine and cocaine (CART) [1, 2] This pathway contains neurons capable of stimulating food intake through the secretion of orexigenic peptides such as neuropeptide Y (NPY) and the peptide associated with agouti (AgRP). As well as kinetics properties, we hypothesized that the inhibition of MCT4 can produce differential alterations in feeding behavior, in comparison with MCT1 [11] To test this hypothesis, we inhibited the expression of MCT4 (AdshMCT4) in tanycytes using a similar experimental approach. We evaluated the expression of neuropeptides in response to i.c.v. glucose injection after MCT4 or MCT1 and MCT4 inhibitions
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