High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity

• Published in: PloS one Vol. 10; no. 5; p. e0128274
• Main Authors: Liu, Zhigang, Patil, Ishan Y, Jiang, Tianyi, Sancheti, Harsh, Walsh, John P, Stiles, Bangyan L, Yin, Fei, Cadenas, Enrique
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29-05-2015; Public Library of Science (PLoS)
• Subjects: AKT protein; Alzheimer's disease; Analysis; Animals; Apoptosis; Biosynthesis; Blood glucose; Blood Glucose - metabolism; Body weight; Brain; Care and treatment; Cell survival; Cyclic AMP response element-binding protein; Deactivation; Development and progression; Diabetes; Diet; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Electrophysiology; Extracellular signal-regulated kinase; Fasting; Glucose; Glucose tolerance; Glucose Transporter Type 3 - metabolism; Glucose Transporter Type 4 - metabolism; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; High fat diet; Homeostasis; Impact resistance; Impairment; Inactivation; Inflammation; Insulin; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; JNK protein; Kinases; Learning; Liver; Liver - metabolism; Liver - pathology; Localization; Long-term potentiation; MAP Kinase Signaling System - drug effects; Memory; Metabolism; Mice; Mitochondria; Neuronal Plasticity - drug effects; NF-kappa B - metabolism; NF-κB protein; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Obesity; Oxidative stress; Oxygen; Oxygen consumption; Patient outcomes; Pharmaceutical sciences; Pharmacology; Pharmacy; Phosphorylation; Plasticity; Proteins; Risk factors; Rodents; Substrates; Synaptic plasticity; Triglycerides; Triglycerides - blood; Tumor necrosis factor-TNF; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128274

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.