Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

Abstract

Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinson's disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IκBα in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure.

Fig. 1.

Food intake and body weight. High-fat (HF) feeding affected body weight (A), and food intake (B). HF-fed animals weighed more than chow-fed rats, although food intake in the HF group was increased only initially and was affected to a greater extent by the lesion. Values are expressed as means ± SE for 8–10 rats per group. *P < 0.05 chow vs. HF.

Fig. 2.

Intraperitoneal glucose tolerance test (IPGTT). After an overnight (12 h) fast, an intraperitoneal injection of 60% glucose was administered at 2 g glucose/kg body wt. Insulin (A) and glucose (B) were measured in tail blood at six time points: 0, 15, 45, 60, 90, and 120 min after the glucose bolus (injection at t = 0). The HF group exhibited significantly higher glucose values 90 and 120 min following the bolus. Serum insulin levels were significantly higher at the fasting (0) time point and 120 min postbolus. *P ≤ 0.05.

Fig. 3.

HF diet affects glucose transport in skeletal muscle. Glucose transport was measured to further characterize the effect of diet on peripheral insulin sensitivity. 2-Deoxyglucose uptake was determined in extensor digitorum longus (EDL) (A) and soleus (B) muscles incubated in the absence (solid bars) or presence (open bars) of 2 mU/ml insulin. Insulin significantly increased glucose uptake in both the EDL and soleus muscles of all rats. In the EDL muscle, insulin stimulated glucose transport in HF rats was less than controls, indicating insulin resistance. Values are expressed as means ± SE for 10–12 muscles per group. *P < 0.05 basal vs. insulin, #P < 0.05 interaction effect between group and insulin.

Fig. 4.

Effects of HF diet and 6-hydroxydopamine (6-OHDA) on tissue dopamine (DA) content. DA content in the right (lesioned) striatum was divided by DA levels in left (nonlesioned) striatum to obtain a percent depletion for each rat. Percent depletion was calculated in two different tissues: the substantia nigra (SN) (A), and striatum (B). HF-fed animals exhibited significantly greater DA depletion than controls in both tissues. Values are expressed as means ± SE for 8–10 samples per group. *P < 0.05 chow vs. HF.

Fig. 5.

Systemic effects of HF feeding correlate with DA depletion. HF-fed rats exhibited a higher HOMA-IR value compared with chow-fed rats (A), indicating impaired insulin sensitivity. In all animals, there was a significant positive correlation between HOMA-IR and DA depletion levels in SN (B) and striatum (C). The HF diet group also exhibited higher epidydymal fat weight as expected (D). Like HOMA-IR, epidydymal fat also correlated significantly with DA depletion in both tissues (E, F). Values are expressed as means ± SE; 8–10 rats per group. *P < 0.05 chow vs. HF.

Fig. 6.

Effects of HF diet and 6-OHDA on 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio. The ratio of DOPAC divided by DA was calculated as an estimate of DA turnover in the SN (A) and the striatum (B). In the SN, DA turnover was significantly increased in the lesioned hemisphere of HF-fed animals, but it was decreased in the lesioned hemisphere of chow-fed animals. No difference between groups was observed in the striatum. Values are expressed as means ± SE for 8–10 samples per group. *P < 0.05 chow vs. HF, #P < 0.05 interaction effect between group and hemisphere.

Fig. 7.

HF feeding decreases heat shock protein (Hsp) activation and IκBα protein levels. Activation of heat shock protein 25 (A) and IκBα expression (B) were analyzed in the SN. There was significantly less activation of Hsp25 in HF-fed animals compared with the chow group. The HF group also exhibited a strong trend (P = 0.056) for a decrease in IκBα protein levels compared with chow rats. No difference between hemispheres was observed for either protein measure. Values are expressed as means ± SE for 5–7 samples per group. *P < 0.05 chow vs. HF.