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Obesity and Hypertriglyceridemia Produce Cognitive Impairment
Open accessAbstract
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.
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“Obesity and hypertriglyceridemia produce cognitive impairment in mice, including reduced lever pressing for food reward ([59](#B59)), and epidemiological studies show an association of body mass index and risk of Parkinson disease and cognitive decline ([85](#B85)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [59]
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Sanjana, F., Delgorio, P. L., Hiscox, L. V., DeConne, T. M., Hobson, J. C., Cohen, M. L., Johnson, C. L., & Martens, C. R. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20968032 · Cited by 28
“Although previous studies have demonstrated a similar link between serum lipids and memory function 11,13,14 , our study is the first to relate these important cardiometabolic risk factors to markers of HC tissue integrity in otherwise healthy humans.”
Karczewski, J., Zielińska, A., Staszewski, R., Eder, P., Dobrowolska, A., & Souto, E. B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116145 · Cited by 27
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“So TGs are likely a major cause of the cognitive disturbances in diet-induced obesity (Farr et al., 2008).”
Effects of diet and behavioral enrichment on free fatty acids in the aged canine brain
Snigdha, S., Astarita, G., Piomelli, D., & Cotman, C. W. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.002 · Cited by 27
“…SCD is emerging as a promising therapeutic target for the treatment of diabetes, hyperlipidemia and obesity (Li et al., 2002, Doherty et al., 2008, Farr et al., 2008, Guo et al., 2008, Kalra, 2008, Signore et al., 2008, Holden et al., 2009, Lieb et al., 2009, Moult et al., 2009, Solovyova et al.,…”
Valladolid‐Acebes, I. (2024) · Biomedicines · doi:10.3390/biomedicines12112422 · Cited by 28
Fraga, M. C., de Moura, E. G., Silva, J. O., Bonomo, I. T., Filgueiras, C. C., Abreu‐Villaça, Y., Passos, M. C. F., Lisboa, P. C., & Manhães, A. C. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.07.007 · Cited by 26
Remodeling of brain lipidome in methamphetamine-sensitized mice
Jiang, L., Gu, H., Lin, Y., Xu, W., Zhu, R., Kong, J., Luo, L., Long, H., Liu, B., Chen, B., et al. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2017.07.214 · Cited by 27
Ebrahim, H. A., El‐Gamal, R., & Sherif, R. (2021) · Cells Tissues Organs · doi:10.1159/000519088 · Cited by 28
“Excessive adipose tissue is metabolically active and releases pro-inflammatory mediators triggering a peripheral and central state of inflammation [Farr et al., 2008; Milanski et al., 2009; Pistell et al., 2010].”
BackgroundCombination of Spirulina with glycyrrhizin prevents cognitive dysfunction in aged obese rats
Subramanian, S., & Madhavadas, S. (2015) · Indian Journal of Pharmacology · doi:10.4103/0253-7613.150327 · Cited by 26
“The animal studies have shown that high fructose diet induced obesity led to smaller volumes of hippocampus, the brain region critical for learning and memory, with reduced hippocampal synaptic plasticity which may affect memory and cognition.[19,20] ACh is a key neurotransmitter in hippocampal cholinergic transmissio…”
BackgroundSetkowicz, Z., Gaździńska, A., Osoba, J. J., Karwowska, K., Majka, P., Orzel, J., Kossowski, B., Bogorodzki, P., Janeczko, K. J., Wyleżoł, M., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139987 · Cited by 26
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“…al., 2008; Winocur et al., 2005), and have higher cognitive impairments than wild type mice, especially in obese rats induced by high-fat diets (HFDs) (Farr et al., 2008; Greenwood and Winocur, 1996; Molteni et al., 2002; Stranahan et al., 2008; Winocur and Greenwood, 2005; Winocur et al., 2005).”
BackgroundInfluentialBlood-Based Biomarkers for Predictive Diagnosis of Cognitive Impairment in a Pakistani Population
Iqbal, G., Braidy, N., & Ahmed, T. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00223 · Cited by 25
“Triglycerides mediate CI, possibly by impairing maintenance of the N-methyl-D-aspartate component of hippocampal long-term potentiation and increasing oxidative stress (Razay et al., 2007; Farr et al., 2008).”
BackgroundKawamura, N., Katsuura, G., Yamada-Goto, N., Novianti, E., Inui, A., & Asakawa, A. (2021) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001492 · Cited by 26
Morley, J. E., & Sinclair, A. J. (2009) · Age and Ageing · doi:10.1093/ageing/afp105 · Cited by 25
“This could be due to the fact that high triglycerides have been demonstrated to impair cognition [27].”
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“Meanwhile, excessive energy intake impairs the structure and function of the hippocampus, including synaptic plasticity and neurogenesis, which are associated with cognition [10].”
BackgroundAcademic achievement, BMI, and fast food intake of American and Japanese college students
Kobayashi, F. (2009) · Nutrition & Food Science · doi:10.1108/00346650910992213 · Cited by 24
“Recent research indicated that obese mice showed lower learning and memory functions than normal weight mice ( Farr et al. , 2008”
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Altered motivation masks appetitive learning potential of obese mice
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“Conditioned learning, where individuals associate environmental cues with receipt of a reward, forms an important part of hedonic mechanisms; the latter contribute to the development of human overweight and obesity by driving excessive eating in what may become a vicious cycle.”
BackgroundContu, L., Nizari, S., Heath, C. J., & Hawkes, C. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01045 · Cited by 22
Waters, D. L., Vlietstra, L., Qualls, C., Morley, J. E., & Vellas, B. J. (2020) · GeroScience · doi:10.1007/s11357-020-00163-7 · Cited by 22
“This is also in line with what is previously shown in both human and animal studies that obesity is associated with cognitive impairment and the administration of triglycerides to mice decreases the learning and memory and impairs long-term potential (Farr et al. 2008; Morley and Banks 2010).”
Self-citationAltered Brain Cholinergic and Synaptic Markers in Obese Zucker Rats
Martinelli, I., Tomassoni, D., Roy, P., Amenta, F., & Tayebati, S. K. (2021) · Cells · doi:10.3390/cells10102528 · Cited by 21
Pan, X., Luo, Y., Zhao, D., & Zhang, L. (2022) · BMC Geriatrics · doi:10.1186/s12877-022-03375-y · Cited by 22
Sachdeva, A. K., Dharavath, R. N., & Chopra, K. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2018.06.966 · Cited by 21
Behavioral profile of intermittent vs continuous access to a high fat diet during adolescence
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“Long-term dietary intake of elevated levels of refined sugars and fats is among the factors causing cognitive impairment [28], whereas compounds in fruits and vegetables have been shown to be beneficial in preventing or decreasing cognitive impairment [12].”
BackgroundSuperAgers and centenarians, dynamics of healthy ageing with cognitive resilience
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Patient Safety Considerations in the Rehabilitation of the Individual with Cognitive Impairment
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Metadata
- Authors
- Farr, S. A., Yamada, K. A., Butterfield, D. A., Abdul, H. M., Xu, L., Miller, N. E., Banks, W. A., & Morley, J. E.
- Affiliations
- St. Louis VA Medical Center (US)
- Washington University in St. Louis (US)
- University of Kentucky (US)
- Department of Chemistry and Center of Membrane Sciences (D.A.B., H.M.A.), University of Kentucky, Lexington, Kentucky 40536
- 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
- Corresponding author
- Banks, William A.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-02-14
- Volume
- 149
- Issue
- 5
- Pages
- 2628-2636
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2329289
- OpenAlex
- W2146978742
- Cited by
- 382
- References
- 37
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 17 · 2022: 23 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 26 · 2017: 26 · 2016: 34 · 2015: 27 · 2014: 29 · 2013: 24 · 2012: 20
- FWCI
- 9.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- U.S. Public Health Service (051334, 42774)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- obesity, hypertriglyceridemia, cognitive impairment, triglycerides, metabolic syndrome X, leptin resistance, dyslipidemia, gemfibrozil, triolein, palmitate, NMDA receptor, hippocampal long-term potentiation, oxidative stress, avoidance learning, Morris water maze, food reward
- MeSH terms
- Animals, Hypolipidemic Agents, Avoidance Learning, Cognition Disorders, Diet, Atherogenic, Male, Memory, Mice, Inbred Strains, Obesity, Swimming, Triolein, Lipid Peroxidation, Hypertriglyceridemia, Gemfibrozil, Maze Learning, Excitatory Postsynaptic Potentials, Mice
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