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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

Mody, N, Agouni, Abdelali, Mcilroy, GD, Platt, B and Delibegovic, M (2011) 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 DIABETOLOGIA, 54 (8). pp. 2143-2151.

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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 (APPSWE) and presenilin 1 (PSEN1A246E) (APP/PSEN1), or PSEN1A246E 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.

Item Type: Article
Authors :
NameEmailORCID
Mody, NUNSPECIFIEDUNSPECIFIED
Agouni, Abdelalia.agouni@surrey.ac.ukUNSPECIFIED
Mcilroy, GDUNSPECIFIEDUNSPECIFIED
Platt, BUNSPECIFIEDUNSPECIFIED
Delibegovic, MUNSPECIFIEDUNSPECIFIED
Date : 3 May 2011
Identification Number : 10.1007/s00125-011-2160-2
Copyright Disclaimer : © Springer-Verlag 2011
Uncontrolled Keywords : Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Diet-induced obesity, Insulin resistance, Glucose intolerance, Type 2 diabetes, Alzheimer's disease, Human mutations, Transgenes, APPSWE/PS1 BIGENIC MODEL, LIVER-SPECIFIC DELETION, INSULIN-RESISTANCE, TRANSGENIC MICE, IN-VIVO, AMYLOID DEPOSITION, INTRANASAL INSULIN, METABOLIC SYNDROME, MEMORY DEFICITS, RETINOL-BINDING-PROTEIN-4
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 16 Aug 2017 12:04
Last Modified : 16 Aug 2017 12:04
URI: http://epubs.surrey.ac.uk/id/eprint/158275

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