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Cited by 78Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Obesity exacerbates chemically induced neurodegeneration

Sriram, K, Benkovic, S.A, Miller, D.B, O’Callaghan, J.P·2002·Neuroscience
DOI 10.1016/s0306-4522(02)00306-8
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Abstract

Obesity is a major risk factor associated with a variety of human disorders. While its involvement in disorders such as diabetes, coronary heart disease and cancer have been well characterized, it remains to be determined if obesity has a detrimental effect on the nervous system. To address this issue we determined whether obesity serves as a risk factor for neurotoxicity. Model neurotoxicants, methamphetamine (METH) and kainic acid (KA), which are known to cause selective neurodegeneration of anatomically distinct areas of the brain, were evaluated using an animal model of obesity, the ob/ob mouse. Administration of METH and KA resulted in mortality among ob/ob mice but not among their lean littermates. While METH caused dopaminergic nerve terminal degeneration as indicated by decreased striatal dopamine (49%) and tyrosine hydroxylase protein (68%), as well as an increase in glial fibrillary acidic protein by 313% in the lean mice, these effects were exacerbated under the obese condition (96%, 86% and 602%, respectively). Similarly, a dosage of KA that did not increase glial fibrillary acidic protein in lean mice increased the hippocampal content of this protein (93%) in ob/ob mice. KA treatment resulted in extensive neuronal degeneration as determined by Fluoro-Jade B staining, decreased hippocampal microtubule-associated protein-2 immunoreactivity and increased reactive gliosis in ob/ob mice. The neurotoxic outcome in ob/ob mice remained exacerbated even when lean and ob/ob mice were dosed with METH or KA based only on a lean body mass. Administration of METH or KA resulted in up-regulation of the mitochondrial uncoupling protein-2 to a greater extent in the ob/ob mice, an effect known to reduce ATP yield and facilitate oxidative stress and mitochondrial dysfunction. These events may underlie the enhanced neurotoxicity seen in the obese mice. In summary, our results implicate obesity as a risk factor associated with chemical- and possibly disease-induced neurodegeneration.

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  • The obese, leptin-deficient mouse is much more sensitive to chemically-induced neurodegeneration such as metamphetamine-induced dopamine nerve terminal degeneration as indicated by reduced striatal dopamine levels.

    “The obese, leptin-deficient mouse is much more sensitive to chemically-induced neurodegeneration such as metamphetamine-induced dopamine nerve terminal degeneration as indicated by reduced striatal dopamine levels ([170](#B170)).”

    From Food reward, hyperphagia, and obesity (2011) · cites this paper as [170]

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Authors
Sriram, K., Benkovic, S. A., Miller, D. B., & O’Callaghan, J. P.
Affiliations
Centers for Disease Control and Prevention (US)
ORCID
Venue
Neuroscience
Publisher
Elsevier BV
Published
2002-12
Volume
115
Issue
4
Pages
1335-1346
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/s0306-4522(02)00306-8
OpenAlex
W2057359899
Cited by
78
References
64
Citations by year
2026: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 6 · 2015: 2 · 2014: 2 · 2013: 5
FWCI
2.00
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
obesity, neurodegeneration, neurotoxicity, ob/ob mice, methamphetamine, kainic acid, striatal dopamine, tyrosine hydroxylase, glial fibrillary acidic protein, reactive gliosis, hippocampal neuronal degeneration, MAP2, mitochondrial uncoupling protein 2, oxidative stress, mitochondrial dysfunction, risk factors
MeSH terms
Uncoupling Protein 2, Animals, Astrocytes, Brain, Disease Models, Animal, Dopamine, Female, Glial Fibrillary Acidic Protein, Hippocampus, Immunohistochemistry, Ion Channels, Kainic Acid, Methamphetamine, Mice, Obese, Microtubule-Associated Proteins, Neurons, Neurotoxins, Obesity, Proteins, Neostriatum, Presynaptic Terminals, Neurodegenerative Diseases, Neurotoxicity Syndromes, Mitochondrial Proteins, Membrane Transport Proteins, Mice

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