Lactate activates hypothalamic POMC neurons by intercellular signaling

Ordenes, Patricio; Villar, Pablo S.; Tarifeño-Saldivia, Estefanía; Salgado, Magdiel; Elizondo‐Vega, Roberto; Araneda, Ricardo C.; García-Robles, María De Los Ángeles

doi:10.1038/s41598-021-00947-7

Cited by 23 publications

(12 citation statements)

References 62 publications

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“…Importantly, microstructure analyses demonstrated that this effect was due to a decrease in the induction of satiety 14 . Similar results were obtained using electrophysiological recordings, showing that POMC neurons are activated by glucose and this response was lost when MCT1-4 were inhibited in tanycytes 19 or by direct incubation of hypothalamic slices with L-lactate 22 . Here, we demonstrated that the modulation of glucose metabolism in tanycytes is important for the satiety response using behaviour studies.…”

Section: Discussionsupporting

confidence: 82%

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

Salgado¹,

Elizondo‐Vega²,

Villar³

et al. 2022

Theranostics

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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.

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Section: Discussionsupporting

confidence: 82%

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

Salgado¹,

Elizondo‐Vega²,

Villar³

et al. 2022

Theranostics

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“…In agreement with these findings, we confirmed that the levels of hypothalamic leucine were elevated in fasted mice retaining altered metabolic activity, such as hyperphagia and hypoglycemia. Lactate exerts neuronal activity in hypothalamic neurons that controls whole-body energy metabolism, and the shuttling of lactate from tanycytes to POMC neurons is functionally linked to the control of feeding behavior and energy expenditure [ 17 , 18 ]. These previous findings are consistent with our metabolomics results revealing a reduced level of lactate in the hypothalamus of fasted mice.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profiling of the Hypothalamus of Mice during Short-Term Food Deprivation

et al. 2022

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Nutrient availability and utilization in hypothalamic cells are directly associated with the regulation of whole-body energy homeostasis. Thus, establishing metabolic profiling in the hypothalamus in response to metabolic shift is valuable to better understand the underlying mechanism of appetite regulation. In the present study, we evaluate the alteration of lipophilic and hydrophilic metabolites in both the hypothalamus and serum of fasted mice. Fasted mice displayed an elevated ketone body and decreased lactate levels in the hypothalamus. In support of the metabolite data, we further confirmed that short-term food deprivation resulted in the altered expression of genes involved in cellular metabolic processes, including the shuttling of fuel sources and the production of monocarboxylates in hypothalamic astrocytes. Overall, the current study provides useful information to close the gap in our understanding of the molecular and cellular mechanisms underlying hypothalamic control of whole-body energy metabolism.

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“…Such POMC-EGFP mice may be useful in studying hypothalamic neuronal signaling pathways involved in the regulation of glucose homeostasis, leptin activity, feeding behavior, obesity, and depression. Studies using POMC-EGFP mice demonstrated that lactate plays a role of an intercellular messenger in astrocyte-neuron intercellular communication and the regulation of food intake ( Ordenes et al, 2021 ).…”

Section: Spatiotemporal Targeting Of Fluorescent Probesmentioning

confidence: 99%