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GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8825604/ https://www.ncbi.nlm.nih.gov/pubmed/35198055 http://dx.doi.org/10.7150/thno.66634 |
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author | Salgado, Magdiel Elizondo-Vega, Roberto Villar, Pablo S Konar, Macarena Gallegos, Scarlet Tarifeño-Saldivia, Estefanía Luz-Crawford, Patricia Aguayo, Luis G. Araneda, Ricardo C. Uribe, Elena García-Robles, María Ángeles |
author_facet | Salgado, Magdiel Elizondo-Vega, Roberto Villar, Pablo S Konar, Macarena Gallegos, Scarlet Tarifeño-Saldivia, Estefanía Luz-Crawford, Patricia Aguayo, Luis G. Araneda, Ricardo C. Uribe, Elena García-Robles, María Ángeles |
author_sort | Salgado, Magdiel |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8825604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-88256042022-02-22 GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates Salgado, Magdiel Elizondo-Vega, Roberto Villar, Pablo S Konar, Macarena Gallegos, Scarlet Tarifeño-Saldivia, Estefanía Luz-Crawford, Patricia Aguayo, Luis G. Araneda, Ricardo C. Uribe, Elena García-Robles, María Ángeles Theranostics Research Paper 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. Ivyspring International Publisher 2022-01-03 /pmc/articles/PMC8825604/ /pubmed/35198055 http://dx.doi.org/10.7150/thno.66634 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Salgado, Magdiel Elizondo-Vega, Roberto Villar, Pablo S Konar, Macarena Gallegos, Scarlet Tarifeño-Saldivia, Estefanía Luz-Crawford, Patricia Aguayo, Luis G. Araneda, Ricardo C. Uribe, Elena García-Robles, María Ángeles GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title | GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title_full | GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title_fullStr | GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title_full_unstemmed | GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title_short | GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
title_sort | gkrp-dependent modulation of feeding behavior by tanycyte-released monocarboxylates |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8825604/ https://www.ncbi.nlm.nih.gov/pubmed/35198055 http://dx.doi.org/10.7150/thno.66634 |
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