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

• Published in: International journal of molecular sciences Vol. 19; no. 8; p. 2333
• Main Authors: Lee, Yi-Heng, Hsu, Hao-Chieh, Kao, Pei-Chen, Shiao, Young-Ji, Yeh, Skye Hsin-Hsien, Shie, Feng-Shiun, Hsu, Shu-Meng, Yeh, Chih-Wen, Liu, Hui-Kang, Yang, Shi-Bing, Tsay, Huey-Jen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.08.2018; MDPI
• Subjects: Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - drug effects; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Animals; Arcuate nucleus; Blood Glucose; Diet, High-Fat - adverse effects; Disease Models, Animal; Eating - genetics; Energy balance; Food intake; Glucose; High fat diet; Homeostasis; Humans; Hyperphagia; Hyperphagia - drug therapy; Hyperphagia - genetics; Hyperphagia - pathology; Hypothalamus; Inflammation; Insulin; Insulin - metabolism; Insulin - therapeutic use; Insulin resistance; Insulin Resistance - genetics; Interleukin 6; Leptin; Leptin - metabolism; Leptin - therapeutic use; leptin resistance; Metabolic Syndrome - drug therapy; Metabolic Syndrome - genetics; Metabolic Syndrome - pathology; Metabolism; Mice; Mice, Transgenic; Obesity; Obesity - complications; Obesity - genetics; Obesity - pathology; Pathology; Positron emission; Positron emission tomography; Presenilin 1; Rodents; Transgenic animals; Transgenic mice; leptin resistance; Alzheimer’s disease; insulin resistance; high fat diet; hypothalamus
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19082333

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. [ F]-2-fluoro-2-deoxy-d-glucose ([ F]-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.