Dataset Information

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice.

ABSTRACT: The accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic islets under induction by a high-fat diet plays a critical role in the development of type-2 diabetes mellitus (T2DM). T2DM is a risk factor of late-onset Alzheimer's disease (AD). Nevertheless, whether hIAPP in combination with hyperlipidemia may lead to AD-like pathological changes in the brain remains unclear. hIAPP transgenic mice were fed with a high-fat diet for 6 or 12 months to establish the T2DM model. The accumulation of amylin, the numbers of Fluoro-Jade C (FJC)-positive and ?-gal positive cells, and the deposition level of A?42 in the hippocampi of the transgenic mice were detected by using brain sections. Cytoplasmic and membrane proteins were extracted from the hippocampi of the transgenic mice, and the ratio of membrane GLUT4 expression to cytoplasmic GLUT4 expression was measured through Western blot analysis. Changes in the cognitive functions of hIAPP transgenic mice after 12 months of feeding with a high-fat diet were evaluated. hIAPP transgenic mice fed with a high-fat diet for 6 or 12 months showed elevated blood glucose levels and insulin resistance; increased amylin accumulation, number of FJC-positive and ?-gal positive cells, and A?42 deposition in the hippocampi; and reduced membrane GLUT4 expression levels. hIAPP transgenic mice fed with a high-fat diet for 12 months showed reductions in social cognitive ability and passive learning ability. A high-fat diet increased amylin accumulation in the hippocampi of hIAPP transgenic mice, which presented AD-like pathology and behavior characterized by neural degeneration, brain aging, A?42 deposition, and impaired glucose utilization and cognition.

SUBMITTER: Xi XX

PROVIDER: S-EPMC6718729 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice.

Xi Xiao-Xia XX Sun Jing J Chen Hai-Chao HC Chen An-Di AD Gao Li-Ping LP Yin Jie J Jing Yu-Hong YH

Frontiers in aging neuroscience 20190827

The accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic islets under induction by a high-fat diet plays a critical role in the development of type-2 diabetes mellitus (T2DM). T2DM is a risk factor of late-onset Alzheimer's disease (AD). Nevertheless, whether hIAPP in combination with hyperlipidemia may lead to AD-like pathological changes in the brain remains unclear. hIAPP transgenic mice were fed with a high-fat diet for 6 or 12 months to establish the T2DM model. The accumul ...[more]

PMID: 31507407

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Project description:We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-?, IL-1?, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-?1, ?SMA, TGF-?1, TGF-?2, TGF?RII, PDGF, PDGFR?II, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or fibrosis, while the differential effect of aging on HFD-induced renal injury was not remarkable as shown in the liver.

Project description:Fat-mass and obesity-associated protein (Fto) is highly expressed in the brain including, the hippocampus, and its expression is significantly decreased in the brain of Alzheimer's disease patients. In the present study, we measured Fto immunoreactivity and protein levels in the hippocampus of obese and aged mice, which were induced by high-fat diet for 12 weeks and D-galactose treatment for 10 weeks, respectively. The obesity and aging phenotypes were assessed by physiological parameters and Morris water maze test, respectively. High fat diet fed mice showed significant increases in body weight and blood glucose levels compared to that in the control or D-galactose-induced aged mice. In addition, treatment with D-galactose significantly decreased the spatial memory. Fto immunoreactivity in the control group was mainly detected in the pyramidal cells of the CA1 and CA3 regions and in the granule cells of the dentate gyrus. In the hippocampus of high-fat diet-fed mice, Fto immunoreactive structures were similarly found in the hippocampus compared to that in the control group, but Fto immunoreactivity in high-fat diet-fed mice was also found in the stratum oriens and radiatum of the CA1 and CA3 regions and the polymorphic layer of the dentate gyrus. In the hippocampus of D-galactose-induced aged mice, fewer Fto immunoreactive structures were detected in the granule cell layer of the dentate gyrus compared to the control group. Fto mRNA and protein levels based on quantitative real-time polymerase chain reaction and western blot assays were slightly increased in the hippocampus of high-fat diet-fed mice compared to that in control mice. In addition, Fto mRNA and protein levels were significantly decreased in the aged hippocampus compared to that in the control group. Fto protein levels are susceptible to the aging process, but not in the hippocampus of high-fat diet-induced obesity. The reduction of Fto in aged mice may be associated with reduced memory impairment in mice.

Dataset Information

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice.

Publications

High-Fat Diet Increases Amylin Accumulation in the Hippocampus and Accelerates Brain Aging in hIAPP Transgenic Mice.

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