title: High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.
abstract: High-fat diet (HFD)-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group) or a HFD (60% of calorie from fat; HFD group) for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a) a significant decrease of insulin receptor substrate (IRS-1) phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b) these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c) primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment); this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a) an inactivation of the IRS-1 and, consequentially, (b) a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c) a suppression of the ERK/CREB pathway, and (d) a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity). It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts profoundly on brain activity, i.e., synaptic plasticity.
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America; College of Food Science and Engineering, Northwest A&F University, Yangling, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Ishan Y
authors.initials: IY
authors.lastname: Patil
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Harsh
authors.initials: H
authors.lastname: Sancheti
authors.affiliation: Davis School of Gerontology and Program in Neuroscience, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Bangyan L
authors.initials: BL
authors.lastname: Stiles
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.affiliation: Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, United States of America.
authors.forename: Enrique
authors.initials: E
authors.lastname: Cadenas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology*; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D051274:Glucose Transporter Type 3; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D016328:NF-kappa B; C495689:Slc2a3 protein, mouse; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse