title: Mechanisms involved in cholesterol-induced neuronal insulin resistance.
abstract: Insulin receptors (IRs) are highly expressed in the central nervous system (CNS) and play an important role in normal brain functions, such as learning and memory. Due to the increasing rate of obesity in western societies and overall high fat diets, the incidents of neuronal insulin resistance is also on the rise, but the underlying mechanism is still poorly characterized. We found that cholesterol treatment produces robust insulin signaling resistance that is characterized by the marked reduction in insulin-stimulated tyrosine phosphorylation of the IR and its downstream targets insulin receptor substrate 1 (IRS1) and 2 (IRS2). Surface expression of IRs was also decreased and was correlated with an increase in facilitated receptor endocytosis. Membrane fractionation showed that after cholesterol treatment, the proportion of IRs localized in the lipid raft increased and correspondingly there was a reduction of IRs in the non-raft membrane. Interestingly, we found that IRs in the lipid rafts, unlike their counterparts in the non-raft membrane domain, were essentially unresponsive to insulin stimulation and that a high level of tyrosine phosphatase activity was associated with these raft fractions. Our results suggest that the lipid raft microdomain of the neuronal plasma membrane has a strong influence on IR signaling, and that incorporation of high levels of cholesterol may reduce IR signaling by increasing their representation in lipid rafts. The trapping of the IR in the lipid raft domain may result in its inactivation and promote its endocytosis: effects that could contribute to neuronal insulin resistance in obesity.
authors.affiliation: Brain Research Centre and Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Changiz
authors.initials: C
authors.lastname: Taghibiglou
authors.forename: Clarrisa A
authors.initials: CA
authors.lastname: Bradley
authors.forename: Tara
authors.initials: T
authors.lastname: Gaertner
authors.forename: Yuping
authors.initials: Y
authors.lastname: Li
authors.forename: Yushan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D002784:Cholesterol; D011972:Receptor, Insulin; D017027:Protein Tyrosine Phosphatases