title: Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses.
abstract: Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte-specific ecto-nucleotide pyrophosphate phosphodiesterase over-expressing transgenic (AtENPP1-Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high-fat diet, AtENPP1-Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high-fat diet-fed AtENPP1-Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down-regulation of insulin receptor expression, and up-regulation of the free fatty acid receptor 1.
authors: Division of Endocrinology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Hanaa S
authors: HS
authors: Sallam
authors: Batbayar
authors: B
authors: Tumurbaatar
authors: Wen-Ru
authors: WR
authors: Zhang
authors: Demidmaa
authors: D
authors: Tuvdendorj
authors: Manisha
authors: M
authors: Chandalia
authors: Filippo
authors: F
authors: Tempia
authors: Fernanda
authors: F
authors: Laezza
authors: Giulio
authors: G
authors: Taglialatela
authors: Nicola
authors: N
authors: Abate
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011972:Receptor, Insulin / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011972:Receptor, Insulin
keywords: ENPP1; cognitive dysfunction; glutamate receptors; insulin resistance; lipids; synaptic transmission
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