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.

Figure 1

Effects of obesity and triglycerides on three tasks measuring memory. A, Comparison of obese and normal mice in the T-maze foot shock avoidance test. Obese mice performed less well in both measures of cognition. B, Response to foot shock. Obese mice were more sensitive to foot shock than normal mice. C, Comparison of time to reach the platform in the water maze. Obese mice performed more poorly than the normal mice. D, Comparison of acquisition of the lever press task in obese and normal mice. Obese mice performed more poorly than normal mice. E, Effect of triglyceride lowering with gemfibrozil on acquisition in obese mice. Mice with serum triglycerides lowered with gemfibrozil (Gem) performed better than vehicle (Veh)-treated mice. F, Effect of triolein or palmitate injected into the third ventricle on memory in the T-maze foot shock avoidance test. Triolein but not palmitate impaired memory. *, P < 0.05; **, P < 0.01.

Figure 2

Milk fat and triolein impair LTP maintenance but not post-TBS-induced synaptic potentiation (A–C). A, EPSPs normalized to baseline responses show potentiation after TBS (applied at arrow) in hippocampal slices continuously bathed in ACSF (open circles). Synaptic potentiation persists 60 min after TBS, demonstrating maintenance of LTP. Slices bathed in skim milk in ACSF (1% by volume) also exhibit LTP (open triangles). The bar over the graph indicates when ACSF plus milk was applied. In 1% low-fat milk in ACSF, post-TBS synaptic potentiation is observed but reverts to baseline over approximately 30 min, indicating impaired maintenance of LTP (closed triangles). Note that ACSF plus milk does not affect the baseline responses obtained in ACSF alone (t < 0 min). To the right of the graphs are representative traces before and 60 min after (*) TBS. To the right of graph in A, top panel, 60 min after TBS (*), the EPSP has a larger amplitude and steeper slope than the baseline response, indicating maintenance of LTP. The traces in the lower panel were obtained in 1% low-fat milk in ACSF at baseline and 60 min after TBS (*), demonstrating absent maintenance of LTP. B, If ACSF with skim or low-fat milk is applied 10 min after TBS induction of LTP (bar over graph indicates application of ACSF plus milk), LTP is maintained in ACSF plus skim milk but not in ACSF with low-fat milk. As in A, TBS is applied at the vertical arrow. C, EPSPs obtained in ACSF (t < 0 min) are unchanged after application of 1 mg/ml triolein in ACSF starting at t = 0. Triolein was applied from t = 0 to 75 min (bar over graph). TBS (arrow) results in potentiation, which reverts to baseline within 60 min, demonstrating absent LTP maintenance. Traces to the right of the graph (C) are representative traces at baseline, 30 min after TBS (*), and 60 min after TBS (curved arrow), demonstrating that despite demonstrating post-TBS potentiation, LTP is not maintained 60 min after TBS. Calibration for all traces: 2 msec, 0.2 mV. Skim milk, low-fat milk, and triolein do not affect the EPSP slope, but the NMDA component of the EPSP is significantly inhibited by low-fat milk (D–F). D, Slopes of EPSPs in ACSF alone were compared with EPSPs during 60 min of application of ACSF with 1% by volume skim milk (open triangles), 1% by volume low-fat milk (closed triangles), or 1 mg/ml triolein (open circles). The bar over the graph indicates when ACSF perfusion was switched to ACSF plus milk or triolein. The slopes of the EPSPs, dominated by AMPA receptor mediated depolarization are not significantly different. E, The NMDA component of the EPSP is isolated by removing magnesium from the ACSF and adding NBQX to block the AMPA-mediated component of the EPSP. Glycine is also present to facilitate activation of NMDA receptors. The slope of the isolated NMDA-mediated component of the EPSP in ACSF (solid trace) is reduced in ACSF containing low-fat milk (dotted trace, arrow). Calibration was 5 msec, 0.2 mV. F, Cumulative data indicate that the slope of the NMDA-mediated component of the EPSP is not affected by ACSF plus skim milk (open triangles), but ACSF plus low-fat milk significantly inhibits the NMDA component of the EPSP (closed triangles). The bar over the graph indicates when ACSF plus milk was applied. The inhibition approaches maximum after about 5 min of application, and is reversible within about 20 min of washout with ACSF (open squares). The gray box over the graph applies only to the open squares, indicating when the ACSF plus low-fat milk was transiently applied.

Figure 3

Comparison of the effect of a high-fat diet, compared with normal diet (CON) and high-fat diet together with gemfibrozil (GEM) on parameters of oxidative stress in the brain. *, P < 0.05.