title: Obesity and hypertriglyceridemia produce cognitive impairment.
abstract: Obesity is associated with cognitive impairments. Long-term mechanisms for this association include consequences of hyperglycemia, dyslipidemia, or other factors comprising metabolic syndrome X. We found that hypertriglyceridemia, the main dyslipidemia of metabolic syndrome X, is in part responsible for the leptin resistance seen in obesity. Here we determined whether triglycerides have an immediate and direct effect on cognition. Obese mice showed impaired acquisition in three different cognitive paradigms: the active avoidance T-maze, the Morris water maze, and a food reward lever press. These impairments were not attributable to differences in foot shock sensitivity, swim speed, swimming distance, or voluntary milk consumption. Impaired cognition in obese mice was improved by selectively lowering triglycerides with gemfibrozil. Injection into the brain of the triglyceride triolein, but not of the free fatty acid palmitate, impaired acquisition in normal body weight mice. Triolein or milk (97% of fats are triglycerides), but not skim milk (no triglycerides), impaired maintenance of the N-methyl-d-aspartate component of the hippocampal long-term synaptic potential. Measures of oxidative stress in whole brain were reduced by gemfibrozil. We conclude that triglycerides mediate cognitive impairment as seen in obesity, possibly by impairing maintenance of the N-methyl-d-aspartate component of hippocampal long-term potentiation, and that lowering triglycerides can reverse the cognitive impairment and improve oxidative stress in the brain.
authors.affiliation: Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.forename: Kelvin A
authors.initials: KA
authors.lastname: Yamada
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: H Mohammad
authors.initials: HM
authors.lastname: Abdul
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Miller
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology* / Q000503:physiopathology; D004036:Diet, Atherogenic; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D015248:Gemfibrozil / Q000494:pharmacology; D015228:Hypertriglyceridemia / Q000150:complications* / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D013550:Swimming; D014304:Triolein / Q000494:pharmacology
chemical_list: D000960:Hypolipidemic Agents; D014304:Triolein; D015248:Gemfibrozil