Neurodegeneration in an animal model of Parkinson’s disease is exacerbated by a high-fat diet
Open accessAbstract
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.
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Food and water (type, composition, supplier, and access) affects the threshold for developing parkinsonian symptoms.
“Food and water (type, composition, supplier, and access) | Affects body weight, tumour development, nephropathy severity [181], and the threshold for developing parkinsonian symptoms [182].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [182]
The Abstract concludes that a high-fat diet may lower the threshold for developing Parkinson’s disease, but only in the context of dopamine-specific toxin exposure in rats. It reports greater dopamine depletion, not earlier parkinsonian symptoms: locomotor activity did not differ between diet groups. The paper does not establish effects of water, supplier, or access. (LLM, conf=0.88)
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Preclinical models of disease and multimorbidity with focus upon cardiovascular disease and dementia
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- Authors
- Morris, J. K., Bomhoff, G. L., Stanford, J. A., & Geiger, P. C.
- Affiliations
- Department of Molecular and Integrative Physiology,
- University of Kansas Medical Center (US)
- Corresponding author
- Geiger, Paige C.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2010-10
- Volume
- 299
- Issue
- 4
- Pages
- R1082-R1090
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC2957375
- OpenAlex
- W2161461930
- Cited by
- 163
- References
- 62
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 13 · 2015: 6 · 2014: 10 · 2013: 7 · 2012: 7
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Intellectual and Developmental Disabilities Research Center
- National Institute on Aging (AG026491, K02AG026491, AG 023549, R01AG023549)
- National Center for Research Resources (P20RR016475)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- Parkinson's disease, high-fat diet, insulin resistance, type 2 diabetes, 6-hydroxydopamine, substantia nigra, striatum, oxidative stress, HSP27, IκBα degradation, adiposity, HOMA-IR, insulin-stimulated glucose uptake, locomotor activity, animal models
- MeSH terms
- Animals, Blood Glucose, Body Weight, Cholesterol, Chromatography, High Pressure Liquid, Dietary Fats, Dopamine, Eating, Epididymis, Glucose Tolerance Test, Hydrogen Peroxide, Insulin, Insulin Resistance, Iron, Male, Nerve Degeneration, Neurons, Parkinson Disease, Secondary, Rats, Inbred F344, Substantia Nigra, Sympatholytics, Oxidopamine, Neostriatum, Muscle, Skeletal, Mice, Rats
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