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Fasting upregulates the monocarboxylate transporter Mct1 at the rat blood-brain barrier through Ppar d activation

ABSTRACT: Fasting is increasingly recognized as a potential therapeutic intervention in the field of neurology and psychiatry. However, its impact upon the blood-brain barrier (BBB), which strictly regulates the cerebral uptake of a wide range of endogenous compounds and drugs, is unknown. In this study we used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in rats that were fed ad libitum or fasted for one to three days. Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the monocarboxylate transporter Mct1, which is pivotal for the cerebral uptake of ketone bodies and thus for brain adaptation to fasting. Transcriptional profiling of freshly isolated brain endothelial cells showed that Ppar d, a major lipid sensor, was selectively activated in response to fasting. In primary cultured rat brain endothelial cells, pharmacological agonists and free fatty acids selectively activated Ppar d, resulting in the upregulation of Mct1 expression at the transcriptional and protein level. This was confirmed in vivo, by showing that dosing rats with a specific Ppar d antagonist blocked the upregulation of Mct1 expression and activity induced by fasting. Altogether, our study describes for the first time a selective adaptive response of the brain vasculature to fasting and opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain. To further confirm that the Ppar d pathway is active brain endothelial cells, we exposed pc-CECs to GW0742 in the presence or not of GSK0660 for 48 hours and analyzed the cell lysate using non-targeted quantitative proteomics (n=3).

ORGANISM(S): Cellular Organisms

SUBMITTER: David Gomez-Zepeda, Stefan Tenzer

PROVIDER: PXD044587 | JPOST Repository | Thu Aug 15 00:00:00 BST 2024

REPOSITORIES: jPOST

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Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.

Chasseigneaux Stéphanie S Cochois-Guégan Véronique V Lecorgne Lucas L Lochus Murielle M Nicolic Sophie S Blugeon Corinne C Jourdren Laurent L Gomez-Zepeda David D Tenzer Stefan S Sanquer Sylvia S Nivet-Antoine Valérie V Menet Marie-Claude MC Laplanche Jean-Louis JL Declèves Xavier X Cisternino Salvatore S Saubaméa Bruno B

Fluids and barriers of the CNS 20240408 1

<h4>Background</h4>The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters.<h4>Methods</h4>We used a combination of ...[more]

PMID: 38589879

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