Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet.
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.
Morris
Jill K
JK
Department of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, 66160, USA.
Bomhoff
Gregory L
GL
Stanford
John A
JA
Geiger
Paige C
PC
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology; D004435:Eating / Q000502:physiology; D004822:Epididymis / Q000378:metabolism; D005951:Glucose Tolerance Test; D006861:Hydrogen Peroxide; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D017072:Neostriatum / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000502:physiology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000502:physiology; D013565:Sympatholytics
D001786:Blood Glucose; D004041:Dietary Fats; C045076:Fenton's reagent; D007328:Insulin; D013565:Sympatholytics; D016627:Oxidopamine; D002784:Cholesterol; D006861:Hydrogen Peroxide; D007501:Iron; D004298:Dopamine