title: High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice.
abstract: Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17days or a moderate high fat diet (HFD, 45% kcal by fat) for 8weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS(616)), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors.
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA. Electronic address: steven.arnold@uphs.upenn.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Brookshire
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Carlson
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Browne
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Hala
authors.initials: H
authors.lastname: Kazi
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Bang
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Bo-Ran
authors.initials: BR
authors.lastname: Choi
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: McMullen
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 125 South 31st St, Philadelphia, PA 19104, USA. Electronic address: sangwonk@mail.med.upenn.edu.
authors.forename: Sangwon F
authors.initials: SF
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D006943:Hyperglycemia / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D065852:Spatial Memory / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
keywords: Akt; GSK3; IPMK; Insulin; Insulin receptor substrate 1; Spine; Synapse; Working memory; mTOR