Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

BMC Endocrine Disorders

Research Article

Suzanne M de la Monte¹  Lisa Longato²  Ming Tong³ 

[1] Department of Pathology (Neuropathology), Rhode Island Hospital, 593 Eddy Street, 02903, Providence, RI, USA;Department of Neurology, Rhode Island Hospital, 593 Eddy Street, 02903, Providence, RI, USA;Liver Research Center, Rhode Island Hospital, 55 Claverick Street, 02903, Providence, RI, USA;Pathobiology Program, Brown University, Box G, 222 Richmond Street, 02903, Providence, RI, USA;Warren Alpert Medical School of Brown University, Box G, 97 Waterman Street, 02912, Providence, RI, USA;Liver Research Center, Rhode Island Hospital, 55 Claverick Street, 02903, Providence, RI, USA;Pathobiology Program, Brown University, Box G, 222 Richmond Street, 02903, Providence, RI, USA;Liver Research Center, Rhode Island Hospital, 55 Claverick Street, 02903, Providence, RI, USA;Warren Alpert Medical School of Brown University, Box G, 97 Waterman Street, 02912, Providence, RI, USA;

关键词: Glial Fibrillary Acidic Protein;    Multiple System Atrophy;    Progressive Supranuclear Palsy;    Cerebellar Degeneration;    Glial Fibrillary Acidic Protein Immunoreactivity;   

DOI  :  10.1186/1472-6823-10-4

 received in 2009-02-13, accepted in 2010-03-19,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundType 2 diabetes mellitus (T2DM) and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM.HypothesisLimited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration.MethodsLong Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF) deficiency and resistance in the context of neurodegeneration.ResultsHFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT), which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity), glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats.ConclusionsEarly limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of ceramides and probably other toxic lipids in brain.

【 授权许可】

Unknown   
© Tong et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.