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Obesity and Hypertriglyceridemia Produce Cognitive Impairment

Division of Geriatric Medicine (S.A.F., N.E.M., W.A.B., J.E.M.), Saint Louis University School of Medicine, St. Louis, Missouri 63104; Geriatrics Research Education and Clinical Center (S.A.F., N.E.M., W.A.B., J.E.M.), Veterans Affairs Medical Center, St. Louis, Missouri 63106; Department of Neurology (K.A.Y., L.X.), Washington University School of Medicine, St. Louis, Missouri 63110; and Department of Chemistry and Center of Membrane Sciences (D.A.B., H.M.A.), University of Kentucky, Lexington, Kentucky 40536

Address all correspondence and requests for reprints to: William A. Banks, M.D., Veterans Affairs Medical Center, 915 North Grand Boulevard, St. Louis, Missouri 63106. E-mail: bankswa{at}slu.edu.

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.