Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice

Abstract

One of the tissues or organs affected by diabetes is the nervous system, predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy) but also the central system with impaired learning, memory and mental flexibility. The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but only the C57BL6 mice showed statistically significant hyperglycemia. STZ-diabetic C57BL6 mice developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point. By 6 months on HFD, Swiss Webster mice developed learning and memory deficits in the Barnes maze test, whereas their peripheral nervous system remained normal. In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction, as indicated by nerve conduction slowing and thermal hyperalgesia, but showed normal learning and memory functions. Our data indicate that STZ-induced diabetes or a HFD can damage both peripheral and central nervous systems, but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions and only in Swiss Webster mice. In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype.

Keywords: Glucose; High-fat diet; Insulin; Neuropathy.

Fig. 1.

Metabolic parameters. (A) Body weight, (B) food consumption, (C) blood glucose levels, (D) plasma insulin levels an (E) blood glucose levels after a glucose challenge are shown for C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). *P<0.05, **P<0.01 using Student’s t-test against their respective LFD control.

Fig. 2.

Peripheral neuropathy parameters. (A) Motor nerve conduction velocity and (B) thermal latencies for C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). *P<0.05, **P<0.01 using Student’s t-test against their respective LFD control.

Fig. 3.

Learning and memory behavior. (A) Area under the curve (AUC) of the learning curves over 5 days (learning phase) and (B) time to find the hole after 3 days without exposure to the maze (memory phase) in the Barnes maze test for C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). *P<0.05, using Student’s t-test against their respective LFD control. ^#P<0.05 using one-way ANOVA against C57BL6 LFD.

Fig. 4.

Lipid profile. (A) Plasma triglyceride levels and (B) plasma total cholesterol levels for C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). **P<0.01, ***P<0.001 using Student’s t-test against their respective LFD control. ^###P<0.001 using one-way ANOVA against C57BL6 LFD.

Fig. 5.

Adiponectin profile. (A) Plasma adiponectin levels, (B) adiponectin protein and (C) adiponectin receptor protein levels in hippocampus of C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). **P<0.01 using Student’s t-test against their respective LFD control.

Fig. 6.

Western blot analysis. (A) Phosphorylated insulin receptor, (B) phosphorylated GSK3β, (C) amyloid-β (Aβ; 24 kDa), (D) phosphorylated tau, (E) synaptophysin and (F) actin protein levels normalized against cyclophilin B in the hippocampus of C57BL6 (C57) and Swiss Webster (Swiss) mice on a low-fat diet (LFD) or high-fat diet (HFD). *P<0.05, using Student’s t-test against their respective LFD control. (G) Representative western blot images for the proteins in A to F.