| Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. | |
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MedLine Citation:
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PMID: 20693650 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) are associated with cognitive impairment, brain insulin resistance, and neurodegeneration. Recent studies linked these effects to increased pro-ceramide gene expression in liver and increased ceramide levels in serum. Since ceramides are neurotoxic and cause insulin resistance, we directly examined the role of ceramides as mediators of impaired signaling and central nervous system function using an in vivo model. Long Evans rat pups were administered C2Cer:N-acetylsphinganine or its inactive dihydroceramide analog (C2DCer) by i.p. injection. Rats were subjected to rotarod and Morris water maze tests of motor and cognitive function, and livers and brains were examined for histopathology and integrity of insulin/IGF signaling. C2Cer treatment caused hyperglycemia, hyperlipidemia, and mild steatohepatitis, reduced brain lipid content, and increased ceramide levels in liver, brain, and serum. Quantitative RT-PCR analysis revealed significant alterations in expression of several genes needed for insulin and IGF-I signaling, and multiplex ELISAs demonstrated inhibition of signaling through the insulin or IGF-1 receptors, IRS-1, and Akt in both liver and brain. Ultimately, the toxic ceramides generated in peripheral sources such as liver or adipose tissue caused sustained impairments in neuro-cognitive function and insulin/IGF signaling needed for neuronal survival, plasticity, and myelin maintenance in the brain. These findings support our hypothesis that a liver/peripheral tissue-brain axis of neurodegeneration, effectuated by increased toxic lipid/ceramide production and transport across the blood-brain barrier, could mediate cognitive impairment in T2DM and NASH. |
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Authors:
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Suzanne M de la Monte; Ming Tong; VanAnh Nguyen; Mashiko Setshedi; Lisa Longato; Jack R Wands |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of Alzheimer's disease : JAD Volume: 21 ISSN: 1875-8908 ISO Abbreviation: J. Alzheimers Dis. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-09-16 Completed Date: 2011-01-18 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9814863 Medline TA: J Alzheimers Dis Country: Netherlands |
Other Details:
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Languages: eng Pagination: 967-84 Citation Subset: IM |
Affiliation:
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Department of Pathology (Neuropathology), Rhode Island Hospital, Providence, RI 02903, USA. Suzanne_DeLaMonte_MD@Brown.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Brain / metabolism Ceramides / metabolism*, pharmacology* Enzyme-Linked Immunosorbent Assay Fatty Liver / chemically induced*, metabolism Hyperglycemia / chemically induced*, metabolism Insulin Resistance / physiology* Liver / metabolism Maze Learning / drug effects Motor Skills / drug effects Proto-Oncogene Proteins c-akt / genetics, metabolism Rats Rats, Long-Evans Receptor, IGF Type 1 / genetics, metabolism Receptor, Insulin / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Rotarod Performance Test Statistics, Nonparametric |
| Grant Support | |
ID/Acronym/Agency:
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AA11431/AA/NIAAA NIH HHS; AA12908/AA/NIAAA NIH HHS; K24 AA016126-03/AA/NIAAA NIH HHS; K24 AA016126-04/AA/NIAAA NIH HHS; K24 AA016126-05/AA/NIAAA NIH HHS; K24-AA16126/AA/NIAAA NIH HHS; R01 AA012908-06A1S1/AA/NIAAA NIH HHS; R01 AA012908-07/AA/NIAAA NIH HHS; R01 AA012908-08/AA/NIAAA NIH HHS; R37 AA011431-13/AA/NIAAA NIH HHS; R56 AA011431-12/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ceramides; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, Insulin; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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