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Int. J. Mol. Sci. 2018, 19(8), 2333; https://doi.org/10.3390/ijms19082333

Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

1
Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei 112, Taiwan
2
Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan
3
Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
4
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan
5
Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei 112, Taiwan
6
Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan
7
Aging and Health Research Center, National Yang-Ming University, Taipei 112, Taiwan
8
Center for Neuropsychiatric Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan
9
Ph.D. Program for Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 110, Taiwan
10
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
These authors contributed equally to this manuscript.
*
Authors to whom correspondence should be addressed.
Received: 10 July 2018 / Revised: 2 August 2018 / Accepted: 3 August 2018 / Published: 8 August 2018
(This article belongs to the Special Issue Inflammaging and Oxidative Stress in Aging and Age-Related Disorders)
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Abstract

Alzheimer’s disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis. View Full-Text
Keywords: Alzheimer’s disease; high fat diet; hypothalamus; leptin resistance; insulin resistance Alzheimer’s disease; high fat diet; hypothalamus; leptin resistance; insulin resistance
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lee, Y.-H.; Hsu, H.-C.; Kao, P.-C.; Shiao, Y.-J.; Yeh, S.-H.; Shie, F.-S.; Hsu, S.-M.; Yeh, C.-W.; Liu, H.-K.; Yang, S.-B.; Tsay, H.-J. Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation. Int. J. Mol. Sci. 2018, 19, 2333.

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