Obesity is considered to be a risk factor for neurodegenerative- and psychiatric- diseases including Alzheimer’s disease, schizophrenia, and depression. A high-lard diet is widely used to induce obesity in model animal experiments, which also leads to anxiety-like and depression-like behaviors. However, the contribution of dietary fat source to these abnormal behaviors in obesity is largely unknown.
Sprague-Dawley rats were treated with different types of high-fat (lard and olive oil) diet with high sucrose for more than 8 weeks. Anxiety-like behavior (open-field and social interaction tests) and cognitive function (Y-maze test) after the treatment were analyzed. The expression of mRNA related to neurotransmitter and nutrient transporters in the prefrontal cortex were determined using real-time PCR. Serum lipid species were determined using liquid chromatography with tandem mass spectrometry.
Both high-fat/high-sucrose diets increased body weight (BW), adipose tissue, and serum leptin level. However, the high-lard/high-sucrose (HL/HS), but not high-olive oil/HS, diet induced anxiety-like behavior in open field and social interaction tests. BW and endocrine hormones such as leptin and insulin were not correlated to anxiety-like behavior. HL/HS diet induced an increase in glutamate transporter and a decrease of glutamate receptor mRNA expressions in the prefrontal cortex. Further, serum lysophosphatidyl choline conjugated with several fatty acids was decreased by HL/HS diet. LPC conjugated with eicosapentaenoic acid (EPA) was strongly correlated with anxiety-like behavior.
These results suggest that lipid composition, rather than obesity per se, is a major cause of anxiety-like behavior in high-fat diet-induced obesity. Decreased levels of peripheral LPC conjugated with EPA and altered glutamate system in the prefrontal cortex might be involve in the pathophysiology of the behavioral change.
Subscribe to Journal
Get full journal access for 1 year
only $64.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546.
Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481–6.
Sung KC, Jeong WS, Wild SH, Byrne CD. Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes. Diabetes Care. 2012;35:717–22.
Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67:505–12.
Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. Int J Obes. 2010;34:407–19.
Rouhani MH, Haghighatdoost F, Surkan PJ, Azadbakht L. Associations between dietary energy density and obesity: a systematic review and meta-analysis of observational studies. Nutrition. 2016;32:1037–47.
Gibson-Smith D, Bot M, Brouwer IA, Visser M, Penninx BWJH. Diet quality in persons with and without depressive and anxiety disorders. J Psychiatr Res. 2018;106:1–7.
Morris MC, Tangney CC. Dietary fat composition and dementia risk. Neurobiol Aging. 2014;35:S59–64.
Hidese S, Asano S, Saito K, Sasayama D, Kunugi H. Association of depression with body mass index classification, metabolic disease, and lifestyle: a web-based survey involving 11,876 Japanese people. J Psychiatr Res. 2018;102:23–8.
Kanoski SE, Meisel RL, Mullins AJ, Davidson TL. The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav Brain Res. 2007;182:57–66.
Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58:1632–43.
Catta-Preta M, Martins MA, Cunha Brunini TM, Mendes-Ribeiro AC, Mandarim-de-Lacerda CA, Aguila MB. Modulation of cytokines, resistin, and distribution of adipose tissue in C57BL/6 mice by different high-fat diets. Nutrition. 2012;28:212–9.
Décarie-Spain L, Sharma S, Hryhorczuk C, Issa-Garcia V, Barker PA, Arbour N, et al. Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat. Mol Metab. 2018;10:1–13.
Dutheil S, Ota KT, Wohleb ES, Rasmussen K, Duman RS. High-fat diet induced anxiety and anhedonia: impact on brain homeostasis and inflammation. Neuropsychopharmacology. 2016;41:1874–87.
Aslani S, Vieira N, Marques F, Costa PS, Sousa N, Palha JA. The effect of high-fat diet on rat’s mood, feeding behavior and response to stress. Transl Psychiatry. 2015;5:e684.
Gainey SJ, Kwakwa KA, Bray JK, Pillote MM, Tir VL, Towers AE, et al. Short-term high-fat diet (HFD) induced anxiety-like behaviors and cognitive impairment are improved with treatment by glyburide. Front Behav Neurosci. 2016;10:156.
Valladolid-Acebes I, Merino B, Principato A, Fole A, Barbas C, Lorenzo MP, et al. High-fat diets induce changes in hippocampal glutamate metabolism and neurotransmission. Am J Physiol Endocrinol Metab. 2012;302:E396–402.
Naneix F, Tantot F, Glangetas C, Kaufling J, Janthakhin Y, Boitard C, et al. Impact of early consumption of high-fat diet on the mesolimbic dopaminergic system. eNeuro. 2017;4:ENEURO.0120–17.2017.
Zemdegs J, Quesseveur G, Jarriault D, Pénicaud L, Fioramonti X, Guiard BP. High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice. Br J Pharmacol. 2016;173:2095–110.
de Noronha SR, Campos GV, Abreu AR, de Souza AA, Chianca DA Jr, de Menezes RC. High fat diet induced-obesity facilitates anxiety-like behaviors due to GABAergic impairment within the dorsomedial hypothalamus in rats. Behav Brain Res. 2017;316:38–46.
Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with omega-3 fatty acids in psychiatric disorders: a review of literature data. J Clin Med. 2016;5:E67.
Hsu MC, Tung CY, Chen HE. Omega-3 polyunsaturated fatty acid supplementation in prevention and treatment of maternal depression: putative mechanism and recommendation. J Affect Disord. 2018;238:47–61.
Lonergan PE, Martin DS, Horrobin DF, Lynch MA. Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide-induced dysfunction in rat hippocampus. J Neurochem. 2004;91:20–9.
Kawashima A, Harada T, Kami H, Yano T, Imada K, Mizuguchi K. Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells. J Nutr Biochem. 2010;21:268–77.
Jin Y, Park Y. N-3 polyunsaturated fatty acids and 17β-estradiol injection induce antidepressant-like effects through regulation of serotonergic neurotransmission in ovariectomized rats. J Nutr Biochem. 2015;26:970–7.
Qosa H, Mohamed LA, Batarseh YS, Alqahtani S, Ibrahim B, LeVine H, et al. Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice. J Nutr Biochem. 2015;26:1479–90.
Moon ML, Joesting JJ, Lawson MA, Chiu GS, Blevins NA, Kwakwa KA, et al. The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice. Metabolism. 2014;63:1131–40.
Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014;15:771–85.
Nakajima S, Hira T, Hara H. Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats. Br J Nutr. 2015;113:1477–88.
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.
Fukasawa K, Nakajima S, Gotoh M, Tanaka S, Murofushi H, Murakami-Murofushi K. Qualitative and quantitative comparison of cyclic phosphatidic acid and its related lipid species in rat serum using hydrophilic interaction liquid chromatography with tandem-mass spectrometry. J Chromatogr A. 2018;1567:177–84.
Davidson RJ. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry. 2002;51:68–80.
Welte MA. Expanding roles for lipid droplets. Curr Biol. 2015;25:R470–81.
Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014;509:503–6.
Sugasini D, Thomas R, Yalagala PCR, Tai LM, Subbaiah PV. Dietary docosahexaenoic acid (DHA) as lysophosphatidylcholine, but not as free acid, enriches brain DHA and improves memory in adult mice. Sci Rep. 2017;7:11263.
Yung YC, Stoddard NC, Mirendil H, Chun J. Lysophosphatidic acid signaling in the nervous system. Neuron. 2015;85:669–82.
Posse de Chaves E, Sipione S. Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 2010;584:1748–59.
Sharma S, Fulton S. Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry. Int J Obes. 2013;37:382–9.
Xu TJ, Reichelt AC. Sucrose or sucrose and caffeine differentially impact memory and anxiety-like behaviours, and alter hippocampal parvalbumin and doublecortin. Neuropharmacology. 2018;137:24–32.
Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Krüger P, Fielder E, et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 2018;S1550-4131:30745–9.
Liu J, Garza JC, Bronner J, Kim CS, Zhang W, Lu XY. Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine. Psychopharmacology. 2010;207:535–45.
Van Doorn C, Macht VA, Grillo CA, Reagan LP. Leptin resistance and hippocampal behavioral deficits. Physiol Behav. 2017;176:207–13.
Gancheva S, Galunska B, Zhelyazkova-Savova M. Diets rich in saturated fat and fructose induce anxiety and depression-like behaviours in the rat: is there a role for lipid peroxidation? Int J Exp Pathol. 2017;98:296–306.
Fu Z, Wu J, Nesil T, Li MD, Aylor KW, Liu Z. Long-term high-fat diet induces hippocampal microvascular insulin resistance and cognitive dysfunction. Am J Physiol Endocrinol Metab. 2017;312:E89–97.
Barber MN, Risis S, Yang C, Meikle PJ, Staples M, Febbraio MA, et al. Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes. PLoS ONE. 2012;7:e41456.
Heimerl S, Fischer M, Baessler A, Liebisch G, Sigruener A, Wallner S, et al. Alterations of plasma lysophosphatidylcholine species in obesity and weight loss. PLoS ONE. 2014;9:e111348.
Rauschert S, Uhl O, Koletzko B, Kirchberg F, Mori TA, Huang RC, et al. Lipidomics reveals associations of phospholipids with obesity and insulin resistance in young adults. J Clin Endocrinol Metab. 2016;101:871–9.
Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry. 2010;68:140–7.
Pusceddu MM, Kelly P, Ariffin N, Cryan JF, Clarke G, Dinan TG. n-3 PUFAs have beneficial effects on anxiety and cognition in female rats: Effects of early life stress. Psychoneuroendocrinology. 2015;58:79–90.
Vines A, Delattre AM, Lima MM, Rodrigues LS, Suchecki D, Machado RB, et al. The role of 5-HT A receptors in fish oil-mediated increased BDNF expression in the rat hippocampus and cortex: a possible antidepressant mechanism. Neuropharmacology. 2012;62:184–91.
Berry SE. Triacylglycerol structure and interesterification of palmitic and stearic acid-rich fats: an overview and implications for cardiovascular disease. Nutr Res Rev. 2009;22:3–17.
Weng J, Jiang S, Ding L, Xu Y, Zhu X, Jin P. Autotaxin/lysophosphatidic acid signaling mediates obesity-related cardiomyopathy in mice and human subjects. J Cell Mol Med. 2019;23:1050–8.
Nagle CA, An J, Shiota M, Torres TP, Cline GW, Liu ZX, et al. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. J Biol Chem. 2007;282:14807–15.
Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ. Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J Neurochem. 2012;120:1060–71.
Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science. 2011;333:1903–7.
Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:112–9.
Lombardi G, Leonardi P, Moroni F. Metabotropic glutamate receptors, transmitter output and fatty acids: studies in rat brain slices. Br J Pharmacol. 1996;117:189–95.
Grintal B, Champeil-Potokar G, Lavialle M, Vancassel S, Breton S, Denis I. Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of docosahexaenoic acid. Neurochem Int. 2009;54:535–43.
Xiao Y, Li X. Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res. 1999;846:112–21.
Müller CP, Reichel M, Mühle C, Rhein C, Gulbins E, Kornhuber J. Brain membrane lipids in major depression and anxiety disorders. Biochim Biophys Acta. 2015;1851:1052–65.
This research was supported by JSPS KAKENHI Grant numbers 16K16589 (SN), 26860144 (MG), and the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and development, AMED Grant number 17dm0107100h0002 (HK).
SN designed research; SN, and KF, conducted research and analyzed data; SN wrote the paper; MG, KM-M, and HK reviewed and edited the paper. SN had primary responsibility for final content. All authors read and approved the final paper.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nakajima, S., Fukasawa, K., Gotoh, M. et al. Saturated fatty acid is a principal cause of anxiety-like behavior in diet-induced obese rats in relation to serum lysophosphatidyl choline level. Int J Obes (2019) doi:10.1038/s41366-019-0468-z