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

Nimesh Mody; Abdelali Agouni; George McIlroy; Bettina Platt; Mirela Delibegovic

doi:10.1007/s00125-011-2160-2

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

Nimesh Mody
, Abdelali Agouni
, George McIlroy
, Bettina Platt^* (Corresponding Author)
, Mirela Delibegovic^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2143-2151
Number of pages	9
Journal	Diabetologia
Volume	54
Issue number	8
Early online date	3 May 2011
DOIs	https://doi.org/10.1007/s00125-011-2160-2
Publication status	Published - Aug 2011

Bibliographical note

Acknowledgements
This work was funded by the College of Life Sciences and Medicine, University of Aberdeen, start-up funds to M. Delibegovic. M. Delibegovic is also funded by an RCUK Fellowship, Diabetes UK, British Heart Foundation, and the Royal Society. N. Mody is funded by an intermediate basic research fellowship from the British Heart Foundation. G. D. Mcilroy is funded by a BBSRC postdoctoral training studentship.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

obesity
diabetes
Alzheimer's Disease
transgenic mice

Access to Document

10.1007/s00125-011-2160-2Licence: Unspecified

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this

Mody, N., Agouni, A., McIlroy, G., Platt, B., & 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), 2143-2151. https://doi.org/10.1007/s00125-011-2160-2

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, Nimesh; Agouni, Abdelali; McIlroy, George et al.
In: Diabetologia, Vol. 54, No. 8, 08.2011, p. 2143-2151.

Research output: Contribution to journal › Article › peer-review

Mody, N, Agouni, A, McIlroy, G , Platt, B & 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, vol. 54, no. 8, pp. 2143-2151. https://doi.org/10.1007/s00125-011-2160-2

Mody N, Agouni A, McIlroy G , Platt B , Delibegovic M. 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. 2011 Aug;54(8):2143-2151. Epub 2011 May 3. doi: 10.1007/s00125-011-2160-2

Mody, Nimesh ; Agouni, Abdelali ; McIlroy, George et al. / 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. In: Diabetologia. 2011 ; Vol. 54, No. 8. pp. 2143-2151.

@article{4b7c09d1c223481391dc6453b9c27543,

title = "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",

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.",

keywords = "obesity , diabetes , Alzheimer's Disease , transgenic mice",

author = "Nimesh Mody and Abdelali Agouni and George McIlroy and Bettina Platt and Mirela Delibegovic",

note = "Acknowledgements This work was funded by the College of Life Sciences and Medicine, University of Aberdeen, start-up funds to M. Delibegovic. M. Delibegovic is also funded by an RCUK Fellowship, Diabetes UK, British Heart Foundation, and the Royal Society. N. Mody is funded by an intermediate basic research fellowship from the British Heart Foundation. G. D. Mcilroy is funded by a BBSRC postdoctoral training studentship.",

year = "2011",

month = aug,

doi = "10.1007/s00125-011-2160-2",

language = "English",

volume = "54",

pages = "2143--2151",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "8",

}

TY - JOUR

T1 - 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

AU - Mody, Nimesh

AU - Agouni, Abdelali

AU - McIlroy, George

AU - Platt, Bettina

AU - Delibegovic, Mirela

N1 - Acknowledgements This work was funded by the College of Life Sciences and Medicine, University of Aberdeen, start-up funds to M. Delibegovic. M. Delibegovic is also funded by an RCUK Fellowship, Diabetes UK, British Heart Foundation, and the Royal Society. N. Mody is funded by an intermediate basic research fellowship from the British Heart Foundation. G. D. Mcilroy is funded by a BBSRC postdoctoral training studentship.

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

KW - obesity

KW - diabetes

KW - Alzheimer's Disease

KW - transgenic mice

U2 - 10.1007/s00125-011-2160-2

DO - 10.1007/s00125-011-2160-2

M3 - Article

SN - 0012-186X

VL - 54

SP - 2143

EP - 2151

JO - Diabetologia

JF - Diabetologia

IS - 8

ER -