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.

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

“…Inflammation and subsequent development of insulin resistance has been demonstrated before [51–53]. In this study, hepatic expression of TNFα was unchanged, but the expression of both IL-6 and Hp was significantly upregulated after 6 weeks of HFD feeding.…”

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

“…Even though the relationship between obesity (excess body fat) and neurodegeneration is highly complex, many sources link obesity and high fat consumption with certain neurodegenerative processes [19]. Growing evidence demonstrates that HFD induces insulin resistance, immunological and synaptic alterations in different brain areas [32, 33], and cognitive impairment [34]. …”

Nutritional approaches for managing obesity-associated metabolic diseases

“…For example, HFD reduces insulin receptor (IR) and IRS1/2 expression and/or phosphorylation (Liu, et al 2015), impairs the phosphorylation of PI3K (Zierath, et al 1997), and decreases the translocation of the glucose transporter GLUT4 to the cell membrane (Zierath et al 1997). HFD feeding also directly contributes to insulin resistance in adipose tissue through adipocyte hypertrophy.…”