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Theranostics 2022; 12(4):1518-1536. doi:10.7150/thno.66634 This issue Cite

Research Paper

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

Magdiel Salgado¹, Roberto Elizondo-Vega¹, Pablo S Villar², Macarena Konar^1,5, Scarlet Gallegos⁵, Estefanía Tarifeño-Saldivia^1,3, Patricia Luz-Crawford⁴, Luis G. Aguayo⁵, Ricardo C. Araneda², Elena Uribe³, María Ángeles García-Robles^1✉

1. Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile.
2. Department of Biology, University of Maryland, USA.
3. Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
4. Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.
5. Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile.

✉ Corresponding author: M.A. García-Robles, Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile. mgarciacl, Orcid 0000-0001-8482-0361, Phone number: 56-41-2203805 More

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 (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.

Keywords: Tanycyte, GKRP, lactate, β-hydroxybutyrate, feeding behavior, obesity

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