METABOLIC SYNDROME UPREGULATED BRAIN ARACHIDONIC AND DOCOSAHEXAENOIC ACID METABOLISM IN METABOLIC SYNDROME. In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with disturbed metabolism of arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acids, major polyunsaturated fatty acids (PUFAs) that regulate brain function. Male Wistar rats were fed a control or high-sucrose diet (to induce metabolic syndrome) for 8 weeks. Frozen brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA2 IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA2 VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured after high-energy microwave fixation. The high-sucrose compared with control diet induced insulin resistance, and brain phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA. Eicosanoid concentrations (prostaglandin E2, thromboxane B2 and leukotriene B4) did not change. Thus, upregulated brain AA and DHA metabolism and reduced BDNF and drebrin may contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome. (1) LIVER SYNTHESIS OF DOCOSAHEXAENOIC AND ARACHIDONIC ACIDS IN RATS FED MODEL OF THE METABOLIC SYNDROME. Insulin, which is elevated in the metabolic syndrome, is a key regulator of liver polyunsaturated fatty acid (PUFA) synthesis, due to its direct transcriptional regulation of delta-5 and delta-6 desaturases. The liver is the main site of arachidonic acid (AA) and docosahexaenoic acid (DHA) synthesis from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) respectively. Through secretion into plasma, it supplies them to the brain and heart, which are incapable of de novo AA and DHA synthesis or of elongation of LA or ALA to a significant extent. The livers capacity for AA and DHA synthesis-secretion has not been tested under metabolic conditions of insulin dysregulation, as occurs in the metabolic syndrome. We hypothesized that increased insulin concentrations in rats fed a high-sucrose diet would increase liver synthesis-secretion of AA and DHA from their labeled fatty acid precursors (U-13C-ALA and U-13CLA). We are infusing these heavy-isotope labeled precursors intravenously in unanesthetized rats to test this hypothesis, and using a compartmental model to analyze the data. In addition to identifying abnormalities in PUFA synthesis in the metabolic syndrome, we are applying our infusion method to humans to directly test the AA and DHA liver synthesis-secretion rates. N-3 PUFA DEPRIVATION IN ADOLESCENCE RAT MODEL ADOLESCENT BEHAVIOR AND DOPAMINE AVAILABILITY ARE SENSITIVE TO DIETARY N-3 FATTY ACID CONTENT. Understanding environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. Dietary deficiency of N-3 polyunsaturated fatty acids (PUFAs) has been implicated in schizophrenia and mood disorders, which typically occur during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the assumption that dietary trends toward decreased consumption of these PUFAS began 4-5 decades ago when parents of current adolescents were born. Behavioral performance in a range of tasks as well as markers of dopamine-related neurotransmission were compared in adolescents and adult rats fed n-3 PUFA adequate and deficient diets. In adolescents, n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. N-3 PUFA deficiency may disrupt adolescent behaviors through enhanced dorsal striatal dopamine availability. (2)

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Keleshian, Vasken L; Kellom, Matthew; Kim, Hyung-Wook et al. (2014) Neuropathological responses to chronic NMDA in rats are worsened by dietary n-3 PUFA deprivation but are not ameliorated by fish oil supplementation. PLoS One 9:e95318
Bondi, Corina O; Taha, Ameer Y; Tock, Jody L et al. (2014) Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biol Psychiatry 75:38-46
Rapoport, Stanley I (2013) Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 88:79-85
Yuan, Zhi-Xin; Rapoport, Stanley I; Soldin, Steven J et al. (2013) Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. Biomed Chromatogr 27:422-32
Igarashi, Miki; Chang, Lisa; Ma, Kaizong et al. (2013) Kinetics of eicosapentaenoic acid in brain, heart and liver of conscious rats fed a high n-3 PUFA containing diet. Prostaglandins Leukot Essent Fatty Acids 89:403-12
Igarashi, Miki; Kim, Hyung-Wook; Gao, Fei et al. (2012) Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids. Biochim Biophys Acta 1821:1235-43
Igarashi, Miki; Kim, Hyung-Wook; Chang, Lisa et al. (2012) Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J Neurochem 120:985-97
Ramsden, Christopher E; Ringel, Amit; Feldstein, Ariel E et al. (2012) Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 87:135-41
Kim, Hyung-Wook; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2011) Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation. Prostaglandins Leukot Essent Fatty Acids 85:361-8
Kim, Hyung-Wook; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2011) Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochim Biophys Acta 1811:111-7

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