GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates

Magdiel Salgado; Roberto Elizondo-Vega; Pablo S. Villar; Macarena Konar; Scarlet Gallegos; Estefanía Tarifeño-Saldivia; Patricia Luz-Crawford; Luis G. Aguayo; Ricardo C. Araneda; Elena Uribe; María Ángeles García-Robles

doi:10.7150/thno.66634

GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates

Magdiel Salgado, Roberto Elizondo-Vega, Pablo S. Villar, Macarena Konar, Scarlet Gallegos, Estefanía Tarifeño-Saldivia, Patricia Luz-Crawford, Luis G. Aguayo, Ricardo C. Araneda, Elena Uribe, María Ángeles García-Robles^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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 (GKRPt-OE and GKRPt-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 GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-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.

Original language	English
Pages (from-to)	1518-1536
Number of pages	19
Journal	Theranostics
Volume	12
Issue number	4
DOIs	https://doi.org/10.7150/thno.66634
State	Published - 2022

Bibliographical note

Funding Information:
This work was supported by grants from the Agencia Nacional de Investigación y Desarrollo-ANID: "Fondecyt Regular" Nº1180871(to M.G-R); Beca Doctorado Nacional 2014 Nº 21141042 (to M.S.); “Fondecyt iniciación” Nº 11190690 (to R.E-V). The authors would like to especially thank Vet. Med. Joaquin Rojas (Crea-Vida Biobio, Animal Care Facility) for technical expertise and assistance in the in vivo experiments and Dra. Marjet Heitzer for her helpful discussion and suggestions on the manuscript.

Publisher Copyright:
© 2022 Ivyspring International Publisher. All rights reserved.

Keywords

Feeding behavior
GKRP
Lactate
Obesity
Tanycyte
β-hydroxybutyrate

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7150/thno.66634

Cite this

@article{2802fbbec48f44b1abf18ea1e0f12221,

title = "GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates",

abstract = "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 (GKRPt-OE and GKRPt-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 GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-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.",

keywords = "Feeding behavior, GKRP, Lactate, Obesity, Tanycyte, β-hydroxybutyrate",

author = "Magdiel Salgado and Roberto Elizondo-Vega and Villar, {Pablo S.} and Macarena Konar and Scarlet Gallegos and Estefan{\'i}a Tarife{\~n}o-Saldivia and Patricia Luz-Crawford and Aguayo, {Luis G.} and Araneda, {Ricardo C.} and Elena Uribe and Garc{\'i}a-Robles, {Mar{\'i}a {\'A}ngeles}",

note = "Funding Information: This work was supported by grants from the Agencia Nacional de Investigaci{\'o}n y Desarrollo-ANID: {"}Fondecyt Regular{"} Nº1180871(to M.G-R); Beca Doctorado Nacional 2014 Nº 21141042 (to M.S.); “Fondecyt iniciaci{\'o}n” Nº 11190690 (to R.E-V). The authors would like to especially thank Vet. Med. Joaquin Rojas (Crea-Vida Biobio, Animal Care Facility) for technical expertise and assistance in the in vivo experiments and Dra. Marjet Heitzer for her helpful discussion and suggestions on the manuscript. Publisher Copyright: {\textcopyright} 2022 Ivyspring International Publisher. All rights reserved.",

year = "2022",

doi = "10.7150/thno.66634",

language = "English",

volume = "12",

pages = "1518--1536",

journal = "Theranostics",

issn = "1838-7640",

publisher = "Ivyspring International Publisher",

number = "4",

}

TY - JOUR

T1 - GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates

AU - Salgado, Magdiel

AU - Elizondo-Vega, Roberto

AU - Villar, Pablo S.

AU - Konar, Macarena

AU - Gallegos, Scarlet

AU - Tarifeño-Saldivia, Estefanía

AU - Luz-Crawford, Patricia

AU - Aguayo, Luis G.

AU - Araneda, Ricardo C.

AU - Uribe, Elena

AU - García-Robles, María Ángeles

N1 - Funding Information: This work was supported by grants from the Agencia Nacional de Investigación y Desarrollo-ANID: "Fondecyt Regular" Nº1180871(to M.G-R); Beca Doctorado Nacional 2014 Nº 21141042 (to M.S.); “Fondecyt iniciación” Nº 11190690 (to R.E-V). The authors would like to especially thank Vet. Med. Joaquin Rojas (Crea-Vida Biobio, Animal Care Facility) for technical expertise and assistance in the in vivo experiments and Dra. Marjet Heitzer for her helpful discussion and suggestions on the manuscript. Publisher Copyright: © 2022 Ivyspring International Publisher. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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 (GKRPt-OE and GKRPt-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 GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-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.

AB - 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 (GKRPt-OE and GKRPt-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 GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-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.

KW - Feeding behavior

KW - GKRP

KW - Lactate

KW - Obesity

KW - Tanycyte

KW - β-hydroxybutyrate

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U2 - 10.7150/thno.66634

DO - 10.7150/thno.66634

M3 - Article

AN - SCOPUS:85122692773

SN - 1838-7640

VL - 12

SP - 1518

EP - 1536

JO - Theranostics

JF - Theranostics

IS - 4

ER -

GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates

Abstract

Bibliographical note

Keywords

UN SDGs

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