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

Publisher: Biomed Central Country of Publication: England NLM ID: 101553157 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-8118 (Electronic) Linking ISSN: 20458118 NLM ISO Abbreviation: Fluids Barriers CNS Subsets: MEDLINE

Original Publication: London : Biomed Central

Blood-Brain Barrier*/metabolism ; PPAR delta*/metabolism; Rats ; Male ; Animals ; Endothelial Cells/metabolism ; Membrane Transport Proteins/metabolism ; Brain/metabolism ; Fasting

Background: 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.
Methods: We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion.
Results: 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 ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting.
Conclusions: Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain.
(© 2024. The Author(s).)

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ANR-10-INBS-0009 French government/ANR; ANR-10-INBS-0009 French government/ANR; 031L0217A/B Bundesministerium für Bildung und Forschung; ANR-18-IdEx-0001 French governement/ANR

Keywords: Blood-brain barrier; Endothelial cells; Fasting; MCT1; PPAR δ

0 (PPAR delta)
0 (Membrane Transport Proteins)

Date Created: 20240408 Date Completed: 20240410 Latest Revision: 20240411

20240411

PMC11003008

10.1186/s12987-024-00526-8

38589879