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Diabetologia

Erschienen in:

01.08.2011 | Article

Susceptibility to diet-induced obesity and glucose intolerance in the APP _SWE/PSEN1 _A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

verfasst von: N. Mody, A. Agouni, G. D. Mcilroy, B. Platt, M. Delibegovic

Erschienen in: Diabetologia | Ausgabe 8/2011

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Abstract

Aims/hypothesis

Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer’s disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP _SWE) and presenilin 1 (PSEN1 _A246E) (APP/PSEN1), or PSEN1 _A246E alone, which are well-characterised animal models of Alzheimer’s disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent.

Methods

We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice.

Results

While there were no body weight differences between 16–17- and 20–21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain.

Conclusions/interpretation

Our results indicate that Alzheimer’s disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.

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Titel: Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein
verfasst von: N. Mody
A. Agouni
G. D. Mcilroy
B. Platt
M. Delibegovic
Publikationsdatum: 01.08.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 8/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2160-2

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