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

Abstract

(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 IB␣ 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. dopamine; diabetes; substantia nigra; striatum; insulin resistance CLINICAL STUDIES SUGGEST A LINK between type 2 diabetes (T2D) and Parkinson's disease (PD) (30,46), and between fat intake or adiposity and PD (1, 31, 34). Moreover, it was reported over 40 years ago that greater than 50% of PD patients exhibit abnormal glucose tolerance (4, 10) or diabetes (36). Despite this information, very little is known regarding the relationship of these diseases and the impact of comorbidity on their pathogenesis. By 2025, T2D is estimated to impact 300 million individuals (47), with the elderly at greatest risk (54), the population also at greatest risk for neurodegenerative diseases like PD. For these reasons, understanding the potential for T2D, obesity, high dietary fat intake, and insulin resistance to contribute to PD is critical. Although the exact cause of PD is unknown, various environmental factors such as aging, diet, and environmental toxin exposure have been implicated in contributing to its development (29, 34, 51). The idea that "multiple hits" play a role in PD degeneration is supported by the fact that 80% of dopamine (DA)-producing neurons must be lost for symptoms to appear (50). While diabetes and PD do not invariably coincide, several studies suggest that obesity may potentiate neuronal dysfunction or even neurodegeneration (reviewed in Ref. 11). High-f...

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

“…In this study, rotational behavior was successfully evoked by amphetamine for all experimental rats, indicating unilateral nigrostriatal DA depletion. Similar to our previous studies (Morris et al, 2010), we did not measure significant differences in net rotations between HF and Chow rats. This result was may have been due a lack of diet effect on dopamine receptor stimulation, or that the HF feeding did not influence DA levels greatly enough to lead to behavioral differences.…”

“…Our previous studies have used Fischer 344 rats fed a high-fat diet to model diet-induced obesity with insulin resistance (Morris et al, 2010), and reported that HF feeding can impair glucose tolerance (Gupte et al, 2009). In the current study, we found a reduction in body weight when adult male Fischer 344 rats fed a high-fat diet for 13 weeks were switched to low-fat diet.…”

“…Between 50–80% of patients with PD have abnormal glucose tolerance (Aviles-Olmos et al, 2013). We reported in our previous study that impaired glucose tolerance following a HF diet in middle-aged rats results in significantly greater nigrostriatal DA depletion than chow-fed rats after 6-OHDA treatment (Morris et al, 2010). The fact that striatal DA depletion did not differ significantly between the diet groups may be due to the more severe depletions we achieved in this study.…”

“…Recent studies from our lab and others demonstrate that a high-fat diet increases dopamine (DA) depletion in the 6-hydroxydopamine (6-OHDA) rat and in the MPTP mouse models of PD (Choi et al, 2005, Morris et al, 2010). These effects resemble the effect of aging of the nigrostriatal pathway, which is the leading contributor to PD.…”

GDNF and PD: Less Common Points of View

“…Choi et al, 2005). Likewise, rats under high-fat diet for 5 weeks before 6-OHDA infusion into the medial forebrain bundle exhibit greater dopamine depletion in the substantia nigra and striatum, and increased oxidative stress than control rats (Morris et al, 2010). Confirming the protective effect of caloric restriction, susceptibility to a neurotoxic insult to dopaminergic neurons is exacerbated in obese mice (Sriram et al, 2002).…”