A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse
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 ex...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/10/5365 |
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| author | Antonio J. López-Gambero Cristina Rosell-Valle Dina Medina-Vera Juan Antonio Navarro Antonio Vargas Patricia Rivera Carlos Sanjuan Fernando Rodríguez de Fonseca Juan Suárez |
| author_facet | Antonio J. López-Gambero Cristina Rosell-Valle Dina Medina-Vera Juan Antonio Navarro Antonio Vargas Patricia Rivera Carlos Sanjuan Fernando Rodríguez de Fonseca Juan Suárez |
| author_sort | Antonio J. López-Gambero |
| collection | DOAJ |
| description | 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 (Tg<sup>5xFAD/5xFAD</sup>), heterozygous (Tg<sup>5xFAD/-</sup>), 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 Tg<sup>5xFAD/-</sup> and Tg<sup>5xFAD/5xFAD</sup> mice and increased expression of IL-1β in Tg<sup>5xFAD/5xFAD</sup> mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg<sup>5xFAD/-</sup> and Tg<sup>5xFAD/5xFAD</sup> 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. |
| first_indexed | 2024-03-10T11:14:46Z |
| format | Article |
| id | doaj.art-034c154947c54bb2923a31d831c94733 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:14:46Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-034c154947c54bb2923a31d831c947332023-11-21T20:30:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012210536510.3390/ijms22105365A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD MouseAntonio J. López-Gambero0Cristina Rosell-Valle1Dina Medina-Vera2Juan Antonio Navarro3Antonio Vargas4Patricia Rivera5Carlos Sanjuan6Fernando Rodríguez de Fonseca7Juan Suárez8Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainEURONUTRA S.L, Parque Tecnológico de Andalucía, 29590 Campanillas, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainInstituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, SpainIncreasing 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 (Tg<sup>5xFAD/5xFAD</sup>), heterozygous (Tg<sup>5xFAD/-</sup>), 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 Tg<sup>5xFAD/-</sup> and Tg<sup>5xFAD/5xFAD</sup> mice and increased expression of IL-1β in Tg<sup>5xFAD/5xFAD</sup> mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg<sup>5xFAD/-</sup> and Tg<sup>5xFAD/5xFAD</sup> 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.https://www.mdpi.com/1422-0067/22/10/5365Alzheimer’s disease5xFADinsulin signalingenergy expenditurehypothalamusneuroinflammation |
| spellingShingle | Antonio J. López-Gambero Cristina Rosell-Valle Dina Medina-Vera Juan Antonio Navarro Antonio Vargas Patricia Rivera Carlos Sanjuan Fernando Rodríguez de Fonseca Juan Suárez 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 Alzheimer’s disease 5xFAD insulin signaling energy expenditure hypothalamus neuroinflammation |
| title | A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse |
| title_full | A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse |
| title_fullStr | A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse |
| title_full_unstemmed | A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse |
| title_short | A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse |
| title_sort | negative energy balance is associated with metabolic dysfunctions in the hypothalamus of a humanized preclinical model of alzheimer s disease the 5xfad mouse |
| topic | Alzheimer’s disease 5xFAD insulin signaling energy expenditure hypothalamus neuroinflammation |
| url | https://www.mdpi.com/1422-0067/22/10/5365 |
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