Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance
Rojas, Rocío (Universitat Internacional de Catalunya)
Griñán-Ferré, Christian (Universitat de Barcelona)
Castellanos, Aida (Universitat de Barcelona)
Griego, Ernesto (Albert Einstein College of Medicine (New York, Estats Units d'Amèrica))
Martínez, Marc (Universitat Internacional de Catalunya)
de Dios Navarro-López, Juan (Universidad de Castilla-La Mancha)
Jiménez-Díaz, Lydia (Universidad de Castilla-La Mancha)
Rodríguez Álvarez, José (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Soto del Cerro, David (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Castillo, Pablo E. (Albert Einstein College of Medicine (New York, Estats Units d'Amèrica))
Pallàs, Mercè (Universitat de Barcelona)
Casals, Nuria (Universitat Internacional de Catalunya)
Fadó, Rut (Universitat Internacional de Catalunya)

Date:	2025
Abstract:	The ketogenic diet -high in fat and low in carbohydrates- and intermittent fasting have gained popularity not only for weight management but also for their potential to delay cognitive decline associated with neurodegenerative diseases and aging. However, adherence to these diets remains low due to their restrictive nature and undesirable side effects. Both dietary approaches stimulate hepatic production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons. Here, we investigated whether BHB supplementation could mitigate AMPA receptor trafficking impairments, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as a saturated fat-rich diet. Our results show that, in cultured primary cortical neurons, exposure to palmitic acid decreases surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids and BHB increase these levels. Furthermore, physiological concentrations of BHB (1-2 mM) countered the adverse effects of palmitic acid on synaptic GluA1 and GluA2 levels in hippocampal neurons, restoring AMPA receptor-mediated synaptic transmission. In hippocampal slices, BHB also reversed palmitate-induced impairments in excitability and synaptic plasticity (long-term potentiation; LTP). Additionally, daily intragastric administration of BHB (100 mg/kg/day for two months) prevented deficits in recognition and spatial memory induced by a saturated fat-rich diet (49% of calories from fat) in mice. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptor abundance, synaptic function, and neuroplasticity, shedding light on the potential use of BHB as a dietary supplement to counteract cognitive impairments linked to metabolic diseases.
Grants:	Agencia Estatal de Investigación PID2020-114953RB-C22 Agencia Estatal de Investigación PID2022-139016OA-I00 Agencia Estatal de Investigación PDC2022-133441-I00 Agencia Estatal de Investigación PID2020-119932GB-I00 Ministerio de Sanidad y Consumo CB06/05/0042 Generalitat de Catalunya 2021/SGR-00357
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Beta-hydroxybutyrate ; Palmitic acid ; AMPA receptor ; Saturated fatty acid-rich diet ; Memory ; Synaptic plasticity
Published in:	Molecular metabolism, Vol. 99 (September 2025) , art. 102207, ISSN 2212-8778

DOI: 10.1016/j.molmet.2025.102207
PMID: 40628351

17 p, 2.8 MB

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