title: Obesity exacerbates chemically induced neurodegeneration.
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.
authors.affiliation: HELD/TMBB, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Mailstop L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA.
authors.forename: K
authors.initials: K
authors.lastname: Sriram
authors.forename: S A
authors.initials: SA
authors.lastname: Benkovic
authors.forename: D B
authors.initials: DB
authors.lastname: Miller
authors.forename: J P
authors.initials: JP
authors.lastname: O'Callaghan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007473:Ion Channels; D007608:Kainic Acid / Q000494:pharmacology; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007473:Ion Channels; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009498:Neurotoxins; D011506:Proteins; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D008694:Methamphetamine; D007608:Kainic Acid; D004298:Dopamine