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.
Highlights
Nutritional overload in the form of high dietary intake of fats—modulated by genetic and environmental factors—is associated with a number of somatic disorders, such as obesity, type 2 diabetes mellitus, cardiovascular diseases, and metabolic syndrome
These changes in circulating glucose and insulin levels induced by High-fat diet (HFD) were further reflected in a significant increase in the HOMA-IR index, a quantitative measure of insulin resistance, which appeared at week 8 and augmented at week 12, no change was seen in earlier time points (Fig 1E)
Statistically significant increased triglyceride levels in HFD group were observed at week 4 and 8 time points but not at week 12 (Fig 1F); this was largely due to a significant increase of triglyceride levels in the control mice at week 12 compared to their levels at week 8
Summary
Nutritional overload in the form of high dietary intake of fats—modulated by genetic and environmental factors—is associated with a number of somatic disorders, such as obesity, type 2 diabetes mellitus, cardiovascular diseases, and metabolic syndrome. Blood pressure, and fasting glucose, and reduced HDL cholesterol are recognized as major risk factors for these disorders. These disorders share a common pathological condition, insulin resistance, which entails a progressive reduction in the responsiveness of peripheral tissue to insulin due to nutritional overload, chronic inflammation, dyslipidemia, and hyperglycemia. Insulin resistance is associated with compromised cell metabolism and survival, increased oxidative stress and activated inflammatory responses (cytokine activation). Insulin resistance is a factor of the progression of non-alcoholic fatty liver disease (NAFLD) [3, 4]. The latter progresses with hyperinsulinemia and inhibition of the insulin receptor substrate (IRS) [5, 6]
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