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Article

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse

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Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain
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UGC Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
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Departamento de Biología Celular, Genética y Fisiología, Campus de Teatinos s/n, Universidad de Málaga, Andalucia Tech, 29071 Málaga, Spain
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Facultad de Medicina, Campus de Teatinos s/n, Universidad de Málaga, Andalucia Tech, 29071 Málaga, Spain
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UGC Corazón, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain
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EURONUTRA S.L, Parque Tecnológico de Andalucía, 29590 Campanillas, Spain
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Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, 29071 Málaga, Spain
*
Authors to whom correspondence should be addressed.
Academic Editors: Rosalía Rodríguez-Rodríguez and Cristina Miralpeix
Int. J. Mol. Sci. 2021, 22(10), 5365; https://doi.org/10.3390/ijms22105365
Received: 30 April 2021 / Revised: 15 May 2021 / Accepted: 16 May 2021 / Published: 20 May 2021
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)
Increasing 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. View Full-Text
Keywords: Alzheimer’s disease; 5xFAD; insulin signaling; energy expenditure; hypothalamus; neuroinflammation Alzheimer’s disease; 5xFAD; insulin signaling; energy expenditure; hypothalamus; neuroinflammation
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MDPI and ACS Style

López-Gambero, A.J.; Rosell-Valle, C.; Medina-Vera, D.; Navarro, J.A.; Vargas, A.; Rivera, P.; Sanjuan, C.; Rodríguez de Fonseca, F.; Suárez, J. 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, 22, 5365. https://doi.org/10.3390/ijms22105365

AMA Style

López-Gambero AJ, Rosell-Valle C, Medina-Vera D, Navarro JA, Vargas A, Rivera P, Sanjuan C, Rodríguez de Fonseca F, Suárez J. A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse. International Journal of Molecular Sciences. 2021; 22(10):5365. https://doi.org/10.3390/ijms22105365

Chicago/Turabian Style

López-Gambero, Antonio J., Cristina Rosell-Valle, Dina Medina-Vera, Juan A. Navarro, Antonio Vargas, Patricia Rivera, Carlos Sanjuan, Fernando Rodríguez de Fonseca, and Juan Suárez. 2021. "A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse" International Journal of Molecular Sciences 22, no. 10: 5365. https://doi.org/10.3390/ijms22105365

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