López-Gambero, Antonio J.Rosell-Valle, CristinaMedina-Vera, DinaNavarro, Juan AntonioVargas, AntonioRivera, PatriciaSanjuan, CarlosRodríguez de Fonseca, FernandoSuárez, Juan2024-02-192024-02-192021-05-201661-6596http://hdl.handle.net/10668/4486http://hdl.handle.net/20.500.12105/18351Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.engVoRhttp://creativecommons.org/licenses/by/4.0/Alzheimer’s disease5xFADInsulin signalingEnergy expenditureHypothalamusNeuroinflammationGhrelinInsulin resistanceLeptinOrexinResistinSTAT5 transcription factorBody weightGastric inhibitory polypeptideEnfermedad de AlzheimerProteínas sustrato del receptor de insulinaMetabolismo energéticoHipotálamoEnfermedades neuroinflamatoriasGhrelinaResistencia a la insulinaLeptinaOrexinasResistinaFactor de transcripción STAT5Peso corporalPolipéptido inhibidor gástricoAlzheimer DiseaseAmyloidAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAmyloidogenic ProteinsAnimalsBrainDisease Models, AnimalEnergy MetabolismFemaleGastric Inhibitory PolypeptideGhrelinGlucagon-Like Peptide 1HypothalamusInsulinsMaleMetabolic DiseasesMiceMice, TransgenicPlaque, AmyloidResistinAMP-Activated Protein KinasesAgouti-Related ProteinInsulin ResistanceLeptinSTAT Transcription FactorsEnergy MetabolismBody WeightEatingInterleukin-1TOR Serine-Threonine KinasesAttribution 4.0 International3406516810.3390/ijms221053651422-0067International Journal of Molecular Sciencesopen access