López-Gambero, Antonio J.Rosell-Valle, CristinaMedina-Vera, DinaNavarro, Juan AntonioVargas, AntonioRivera, PatriciaSanjuan, CarlosRodríguez de Fonseca, FernandoSuárez, Juan2022-12-132022-12-132021-05-20López-Gambero AJ, Rosell-Valle C, Medina-Vera D, Navarro JA, Vargas A, Rivera P, et al. A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse. Int J Mol Sci. 2021 May 20;22(10):53651661-6596http://hdl.handle.net/10668/4486Increasing 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.enAtribución 4.0 Internacionalhttp://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 gástricoMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer DiseaseMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::AmyloidMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-PeptidesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid::Amyloidogenic Proteins::Amyloid beta-Protein PrecursorMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid::Amyloidogenic ProteinsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, AnimalMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy MetabolismMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Gastric Inhibitory PolypeptideMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::GhrelinMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Proglucagon::Glucagon-Like Peptides::Glucagon-Like Peptide 1Medical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::HypothalamusMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Peptide Hormones::Pancreatic Hormones::InsulinsMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic DiseasesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, TransgenicMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Plaque, AmyloidMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Adipokines::ResistinMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::AMP-Activated Protein KinasesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Agouti-Related ProteinMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin ResistanceMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Adipokines::LeptinMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Adaptor Proteins, Signal Transducing::STAT Transcription FactorsMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy MetabolismMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body WeightMedical Subject Headings::Phenomena and Processes::Digestive System and Oral Physiological Phenomena::Digestive System Physiological Phenomena::Digestive System Processes::EatingMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-1Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::TOR Serine-Threonine Kinasesresearch article34065168open access10.3390/ijms221053651422-0067PMC8161294