title: A biochemical and functional characterization of diet-induced brain insulin resistance.
abstract: While considerable research has examined diminished insulin responses within peripheral tissues, comparatively little has been done to examine the effects of this metabolic disruption upon the CNS. The present study employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether neural insulin resistance is a component of the metabolic syndrome observed within the fructose-fed (FF) hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in response to insulin were significantly reduced within FF hamsters. Also, insulin-mediated phosphorylation of both residues necessary for activation of the serine-threonine kinase Akt/PKB, a key effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase 1B, which dephosphorylates the IR and IRS-1, were also observed within the cerebral cortex and hippocampus of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling altered synaptic function revealed a significant attenuation of insulin-induced long-term depression, but no effect upon either paired-pulse facilitation or electrically induced long-term potentiation. Collectively, our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute to cognitive impairment.
authors.affiliation: Brain and Behaviour Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Mielke
authors.forename: Changiz
authors.initials: C
authors.lastname: Taghibiglou
authors.forename: Lidong
authors.initials: L
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jia
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004040:Dietary Carbohydrates / Q000494:pharmacology*; D005632:Fructose / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D008647:Mesocricetus; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004040:Dietary Carbohydrates; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D005632:Fructose; D014443:Tyrosine; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases