Interactions of Body Weight Loss with Lipophilic Toxin Storage: Commentary.

A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.

Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children.

OBJECTIVE: Although extant preclinical evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is important for neurodevelopment, little is known about its role in human cortical structural and functional maturation. In the present cross-sectional study, we investigated the relationship between DHA biostatus and functional connectivity in cortical attention networks of typically developing children. METHODS: Male children (aged 8-10 years, n = 36) were divided into 'low-DHA' (n = 18) and 'high-DHA' (n = 18) biostatus groups by a median split of erythrocyte DHA levels. Event-related functional connectivity during the performance of a sustained attention task (identical pairs continuous performance task (CPT-IP)) was conducted using functional magnetic resonance imaging. A voxelwise approach used the anterior cingulate cortex (ACC) as the seed-region. RESULTS: Erythrocyte DHA composition in the low-DHA group (2.6 ± 0.9%) was significantly lower than the high-DHA group (4.1 ± 1.1%, P ≤ 0.0001). Fish intake frequency was greater in the high-DHA group (P = 0.003) and was positively correlated with DHA levels among all subjects. The low-DHA group exhibited reduced functional connectivity between the ACC and the ventrolateral prefrontal cortex, insula, precuneus, superior parietal lobule, middle occipital gyrus, inferior temporal gyrus, and lingual gyrus compared with the high-DHA group (P < 0.05; corrected). The low-DHA group did not exhibit greater ACC functional connectivity with any region compared with the high-DHA group. On the CPT-IP task, the low-DHA group had slower reaction time (P = 0.03) which was inversely correlated with erythrocyte DHA among all subjects. DISCUSSION: These data suggest that low-DHA biostatus is associated with reduced event-related functional connectivity in cortical attention networks of typically developing children.

Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study.

OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H MRS) to investigate the effects of fish oil (FO) supplementation on cortical metabolite concentrations in adolescents with major depressive disorder (MDD). METHODS: Metabolite concentrations were determined by (1)H MRS in the anterior cingulate cortex and bilateral dorsolateral prefrontal cortex (DLPFC) of adolescents with MDD before and following 10-week open-label supplementation with low (2.4 g/day, n = 7) or high (16.2 g/day, n = 7) dose FO. Depressive symptom severity scores and erythrocyte fatty acid levels were also determined. RESULTS: Baseline erythrocyte eicosapentaenoic acid (EPA) composition was positively correlated, and arachidonic acid (AA) and the AA/EPA ratio were inversely correlated, with choline (Cho) concentrations in the right DLPFC. Docosahexaenoic acid (DHA) composition was inversely correlated with myo-inositol (mI) concentrations in the left DLPFC. Erythrocyte EPA and DHA composition increased, and AA decreased, significantly following low-dose and high-dose FO supplementation. In the intent-to-treat sample, depressive symptom severity scores decreased significantly in the high-dose group (-40%, P < 0.0001) and there was a trend in the low-dose group (-20%, P = 0.06). There were no significant baseline-endpoint changes in metabolite levels in each voxel. In the low-dose group there were changes with large effect sizes, including a decrease in mI in the left DLPFC (-12%, P = 0.18, d = 0.8) and increases in glutamate + glutamine (Glx) (+12%, P = 0.19, d = 0.8) and Cho (+15%, P = 0.08, d = 1.2) in the right DLPFC. In the high-dose group, there was a trend for increases in Cho in the right DLPFC (+10%, P = 0.09, d = 1.2). DISCUSSION: These preliminary data suggest that increasing the LCn-3 fatty acid status of adolescent MDD patients is associated with subtle changes in Glx, mI, and Cho concentrations in the DLPFC that warrant further evaluation in a larger controlled trial.

The transport of DDT from chylomicrons to adipocytes does not mimic triacylglycerol transport.

Despite being banned in the U.S., organochlorine toxins such as DDT are frequently detected in human adipose tissue. The main route of exposure is through the consumption of contaminated foods and subsequent intestinal packaging of DDT into chylomicrons. These chylomicrons, which also contain dietary triacylglycerol (TG), are delivered directly to peripheral tissues without first being metabolized by the liver. The physiological process by which these compounds are delivered from chylomicrons to adipose is not well understood, but is clinically relevant since it bypasses first-pass metabolism. Based on its highly lipophilic nature, it has been assumed that DDT is transferred to peripheral tissues similar to TG; however, this has not been measured. Here, we use the lymph fistula rat to isolate chylomicrons containing both DDT and TG. These chylomicrons are the in vivo DDT delivery vehicle. Using 3T3-L1 adipocytes, we investigated the rate at which DDT transfers from chylomicrons to adipocytes, and mediators of this process. This novel approach closely approximates the in vivo DDT exposure route. We show that: 1) DDT repartitions from chylomicrons to adipocytes, 2) this transport does not require hydrolysis of TG within the chylomicron, and is stimulated by the inhibition of LPL, 3) albumin does not inhibit DDT uptake, 4) DDT dissolved in DMSO does not appropriately mimic in vivo DDT transport; and most importantly, 5) DDT uptake from chylomicrons does not mimic the uptake of TG from the same particles. Understanding these factors is important for designing interventions for human populations exposed to DDT.

Low docosahexaenoic acid status is associated with reduced indices in cortical integrity in the anterior cingulate of healthy male children: a 1H MRS Study.

Docosahexaenoic acid (DHA, 22:6n-3) is the principal omega-3 fatty acid in mammalian brain gray matter, and emerging preclinical evidence suggests that DHA has neurotrophic and neuroprotective properties. This study investigated relationships among DHA status, neurocognitive performance, and cortical metabolism measured with proton magnetic resonance spectroscopy (1H MRS) in healthy developing male children (aged 8-10 years, n = 38). Subjects were segregated into low-DHA (n = 19) and high-DHA (n = 19) status groups by a median split of erythrocyte DHA levels. Group differences in 1H MRS indices of cortical metabolism, including choline (Cho), creatine (Cr), glutamine + glutamate + γ-aminobutyric acid (Glx), myo-inositol (mI), and n-acetyl aspartate (NAA), were determined in the right and left dorsolateral prefrontal cortex (R/L-DLPFC, BA9) and bilateral anterior cingulate cortex (ACC, BA32/33). Group differences in neurocognitive performance were evaluated with the Kaufman Brief Intelligence Test and identical-pairs version of the continuous performance task (CPT-IP). Subjects in the low-DHA group consumed fish less frequently (P = 0.02), had slower reaction times on the CPT-IP (P = 0.007), and exhibited lower mI (P = 0.007), NAA (P = 0.007), Cho (P = 0.009), and Cr (P = 0.01) concentrations in the ACC compared with the high-DHA group. There were no group differences in ACC Glx or any metabolite in the L-DLPFC and R-DLPFC. These data indicate that low-DHA status is associated with reduced indices of metabolic function in the ACC and slower reaction time during sustained attention in developing male children.

An assessment of the intestinal lumen as a site for intervention in reducing body burdens of organochlorine compounds.

Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non-biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non-absorbable dietary fats and fat absorption inhibitors, however, can reduce the re-absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine--thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non-absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants.

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid.

Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.

Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion.

BACKGROUND & AIMS: Postprandial hyperlipidemia is a risk factor for atherosclerotic heart disease and is associated with the consumption of high-fat diets and obesity. Bariatric surgeries result in superior and more durable weight loss than dieting. These surgeries are also associated with multiple metabolic improvements, including reduced plasma lipid levels. We investigated whether the beneficial effects of vertical sleeve gastrectomy (VSG) on plasma lipid levels are weight independent. METHODS: VSG was performed on Long-Evans rats with diet-induced obesity. Controls were sham-operated animals who were either pair-fed or ad libitum-fed. We measured fasting and postprandial levels of plasma lipid. To determine hepatic and intestinal triglyceride secretion, we injected the lipase inhibitor poloxamer 407 alone or before oral lipid gavage. (13)C-Triolein was used to estimate postprandial uptake of lipid in the intestine. RESULTS: Rats that received VSG and high-fat diets had markedly lower fasting levels of plasma triglyceride, cholesterol, and phospholipid than obese and lean (pair-fed) controls that were fed high-fat diets. Rats that received VSG had a marked, weight-independent reduction in secretion of intestinal triglycerides. VSG did not alter total intestinal triglyceride levels or size of the cholesterol storage pool nor did it affect the expression of genes in the intestine that control triglyceride metabolism and synthesis. VSG did not affect fasting secretion of triglyceride, liver weight, hepatic lipid storage, or transcription of genes that regulate hepatic lipid processing. CONCLUSIONS: VSG reduced postprandial levels of plasma lipid, independently of body weight. This resulted from reduced intestinal secretion of triglycerides following ingestion of a lipid meal and indicates that VSG has important effects on metabolism.

Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: positive association with stearoyl-CoA desaturase.

Psychiatric patients frequently exhibit long-chain n-3 (LCn-3) fatty acid deficits and elevated triglyceride (TAG) production following chronic exposure to second generation antipsychotics (SGAs). Emerging evidence suggests that SGAs and LCn-3 fatty acids have opposing effects on stearoyl-CoA desaturase-1 (SCD1), which plays a pivotal role in TAG biosynthesis. Here we evaluated whether low LCn-3 fatty acid status would augment elevations in rat liver and plasma TAG concentrations following chronic treatment with the SGA risperidone (RSP), and evaluated relationships with hepatic SCD1 expression and activity indices. In rats maintained on the n-3 fatty acid-fortified (control) diet, chronic RSP treatment significantly increased liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios), and significantly increased liver, but not plasma, TAG concentrations. Rats maintained on the n-3 deficient diet exhibited significantly lower liver and erythrocyte LCn-3 fatty acid levels, and associated elevations in LCn-6/LCn-3 ratio. In n-3 deficient rats, RSP-induced elevations in liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios) and liver and plasma TAG concentrations were significantly greater than those observed in RSP-treated controls. Plasma glucose levels were not altered by diet or RSP, and body weight was lower in RSP- and VEH-treated n-3 deficient rats. These preclinical data support the hypothesis that low n-3 fatty acid status exacerbates RSP-induced hepatic steatosis by augmenting SCD1 expression and activity.

Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity.

BACKGROUND & AIMS: Cholecystokinin (CCK) is a satiation peptide released during meals in response to lipid intake; it regulates pancreatic digestive enzymes that are required for absorption of nutrients. We proposed that mice with a disruption in the CCK gene (CCK knockout [CCK-KO] mice) that were fed a diet of 20% butter fat would have altered fat metabolism. METHODS: We used quantitative magnetic resonance imaging to determine body composition and monitored food intake of CCK-KO mice using an automated measurement system. Intestinal fat absorption and energy expenditure were determined using a noninvasive assessment of intestinal fat absorption and an open circuit calorimeter, respectively. RESULTS: After consuming a high-fat diet for 10 weeks, CCK-KO mice had reduced body weight gain and body fat mass and enlarged adipocytes, despite the same level of food intake as wild-type mice. CCK-KO mice also had defects in fat absorption, especially of long-chain saturated fatty acids, but pancreatic triglyceride lipase did not appear to have a role in the fat malabsorption. Energy expenditure was higher in CCK-KO than wild-type mice, and CCK-KO mice had greater oxidation of carbohydrates while on the high-fat diet. Plasma leptin levels in the CCK-KO mice fed the high-fat diet were markedly lower than in wild-type mice, although levels of insulin, gastric-inhibitory polypeptide, and glucagon-like peptide-1 were normal. CONCLUSIONS: CCK is involved in regulating the metabolic rate and is important for lipid absorption and control of body weight in mice placed on a high-fat diet.

Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity.

Decrease in fat catabolic rate on consuming a high-fat diet contributes to diet-induced obesity. This study used group 1B phospholipase A(2) (Pla2g1b)-deficient mice, which are resistant to hyperglycemia, to test the hypothesis that Pla2g1b and its lipolytic product lysophospholipid suppress hepatic fat utilization and energy metabolism in promoting diet-induced obesity. The metabolic consequences of hypercaloric diet, including body weight gain, energy expenditure, and fatty acid oxidation, were compared between Pla2g1b(+/+) and Pla2g1b(-/-) mice. The Pla2g1b(-/-) mice displayed normal energy balance when fed chow, but were resistant to obesity when challenged with a hypercaloric diet. Obesity resistance in Pla2g1b(-/-) mice is due to their ability to maintain elevated energy expenditure and core body temperature when subjected to hypercaloric diet, which was not observed in Pla2g1b(+/+) mice. The Pla2g1b(-/-) mice also displayed increased postprandial hepatic fat utilization due to increased expression of peroxisome proliferator-activated receptor (PPAR)-alpha, PPAR-delta, PPAR-gamma, cd36/Fat, and Ucp2, which coincided with reduced postprandial plasma lysophospholipid levels. Lysophospholipids produced by Pla2g1b hydrolysis suppress hepatic fat utilization and down-regulate energy expenditure, thereby preventing metabolically beneficial adaptation to a high-fat diet exposure in promoting diet-induced obesity and type 2 diabetes.

Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities.

Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective "jejunization" of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.

Impact of adopting a vegan diet or an olestra supplementation on plasma organochlorine concentrations: results from two pilot studies.

The aim of these studies was to evaluate the potential of some nutritional approaches to prevent or reduce the body load of organochlorines (OC) in humans. Study 1 compared plasma OC concentrations between vegans and omnivores while study 2 verified if the dietary fat substitute olestra could prevent the increase in OC concentrations that is generally observed in response to a weight-reducing programme. In study 1, nine vegans and fifteen omnivores were recruited and the concentrations of twenty-six OC (beta-hexachlorocyclohexane (beta-HCH), p, p'-dichlorodiphenyldichloroethane (p, p'-DDE), p, p'-dichlorodiphenyltrichloroethane (p, p'-DDT), hexachlorobenzene, mirex, aldrin, alpha-chlordane, gamma-chlordane, oxychlordane, cis-nonachlor, trans-nonachlor, polychlorinated biphenyl (PCB) nos. 28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183 and 187, and aroclor 1260) were determined. In study 2, the concentrations of these twenty-six OC were measured before and after weight loss over 3 months in thirty-seven obese men assigned to one of the following treatments: standard group (33 % fat diet; n 13), fat-reduced group (25 % fat diet; n 14) or fat-substituted group (1/3 of dietary lipids substituted by olestra; n 10). In study 1, plasma concentrations of five OC compounds (aroclor 1260 and PCB 99, PCB 138, PCB 153 and PCB 180) were significantly lower in vegans compared with omnivores. In study 2, beta-HCH was the only OC which decreased in the fat-substituted group while increasing in the other two groups (P = 0.045). In conclusion, there was a trend toward lesser contamination in vegans than in omnivores, and olestra had a favourable influence on beta-HCH but did not prevent plasma hyperconcentration of the other OC during ongoing weight loss.

Fat malabsorption in cystic fibrosis: comparison of quantitative fat assay and a novel assay using fecal lauric/behenic acid.

OBJECTIVES: The gold standard for the diagnosis of fat malabsorption, the 72-hour fat balance study, requires a 3-day collection to generate a coefficient of fat absorption (CFA). We hypothesized that a new test using behenic acid (behenate test) as a nonabsorbable lipid marker may provide a facile means to assess fat absorption. The study proposed to answer 2 questions: first, whether the behenate test correlated with the gold standard and, second, whether the CFA improved when taking pancreatic enzymes during meals instead of taking them before meals. PATIENTS AND METHODS: The study compared the behenate test with the gold standard in 15 patients with cystic fibrosis during 3 arms that require 3- to 4-day hospitalization: first, taking pancreatic enzymes before meals; second, taking it during meals; and third, without taking it. RESULTS: The mean CFA was 78.3% when pancreatic enzymes were taken during meals and 80.4% when these enzymes were taken before meals. Correlation between the CFA and the behenate test for collections during all 3 arms was r = 0.219 (P = 0.001). CONCLUSIONS: Timing of ingestion of pancreatic enzymes does not significantly alter the CFA. Although the CFA correlates with the behenate test, the correlation is not robust enough to justify replacement of the gold standard by this test. It is unclear whether the poor correlation between tests relates to intermeal variability in fat excretion or other factors; however, the behenate test may be suitable as a screening test for the detection of fat malabsorption.

GATA4 is essential for jejunal function in mice.

BACKGROUND & AIMS: Although the zinc-finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. METHODS: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. RESULTS: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis revealed that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in messenger RNAs (mRNAs) encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. CONCLUSIONS: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal vs ileal identity.

Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition.

The two-fold higher prevalence rate of major depression in females may involve vulnerability to omega-3 fatty acid deficiency secondary to a dysregulation in ovarian hormones. However, the role of ovarian hormones in the regulation of brain omega-3 fatty acid composition has not been directly evaluated. Here we determined erythrocyte and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition in intact male and female rats, and in chronically ovariectomized (OVX) rats with or without cyclic estradiol treatment (2 microg/4d). All groups were maintained on diets with or without the DHA precursor alpha-linolenic acid (ALA, 18:3n-3). We report that both male (-21%) and OVX (-19%) rats on ALA+ diet exhibited significantly lower erythrocyte DHA composition relative to female controls. Females on ALA+ diet exhibited lower DHA composition in the prefrontal cortex (PFC) relative males (-5%). OVX rats on ALA+ diet exhibited significantly lower DHA composition in the hippocampus (-6%), but not in the PFC, hypothalamus, or midbrain. Lower erythrocyte and hippocampus DHA composition in OVX rats was not prevented by estrogen replacement. All groups maintained on ALA- diet exhibited significantly lower erythrocyte and regional brain DHA composition relative to groups on ALA+ diet, and these reductions were greater in males but not in OVX rats. These preclinical data corroborate clinical evidence for gender differences in peripheral DHA composition (female>male), demonstrate gender differences in PFC DHA composition (male>female), and support a link between ovarian hormones and erythrocyte and region-specific brain DHA composition.

Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition.

Although emerging evidence suggests that schizophrenia (SZ) is associated with peripheral and central polyunsaturated fatty acid (PUFA) deficits, there is currently nothing known about the expression of genes that mediate PUFA biosynthesis in SZ patients. Here we determined Delta5 desaturase (FADS1), Delta6 desaturase (FADS2), elongase (HELO1 [ELOVL5]), peroxisomal (PEX19), and Delta9 desaturase (stearoyl-CoA desaturase, SCD) mRNA expression, and relevant fatty acid product:precursor ratios as estimates of enzyme activities, in the postmortem prefrontal cortex (PFC) of patients with SZ (n=20) and non-psychiatric controls (n=20). After correction for multiple comparisons, FADS2 mRNA expression was significantly greater in SZ patients relative to controls (+36%, p=0.002), and there was a positive trend found for FADS1 (+26%, p=0.15). No differences were found for HELO1 (+10%, p=0.44), PEX19 (+12%, p=0.44), or SCD (-6%, p=0.85). Both male (+34%, p=0.02) and female (+42%, p=0.02) SZ patients exhibited greater FADS2 mRNA expression relative to same-gender controls. Drug-free SZ patients (+37%, p=0.02), and SZ patients treated with typical (+40%, p=0.002) or atypical (+31%, p=0.04) antipsychotics, exhibited greater FADS2 mRNA expression relative to controls. Consistent with increased Delta6 desaturase activity, SZ patients exhibited a greater 20:3/18:2 ratio (+20%, p=0.03) and a positive trend was found for 20:4/18:2 (+13%, p=0.07). These data demonstrate abnormal, potentially compensatory, elevations in Delta6 desaturase (FADS2) expression in the PFC of SZ patients that are independent of gender and antipsychotic medications. Greater Delta6 desaturase expression and activity could have implications for central prostaglandin synthesis and proinflammatory signaling.

Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: evidence for augmented biosynthesis.

Prior clinical studies suggest that chronic treatment with atypical antipsychotic medications increase erythrocyte and postmortem prefrontal cortex (PFC) omega-3 fatty acid composition in patients with schizophrenia (SZ). However, because human tissue phospholipid omega-3 fatty acid composition is potentially influenced by multiple extraneous variables, definitive evaluation of this putative mechanism of action requires an animal model. In the present study, we determined the effects of chronic treatment with the atypical antipsychotic risperidone (RISP, 3.0 mg/kg/d) on erythrocyte and PFC omega-3 fatty acid composition in rats maintained on a diet with or without the dietary omega-3 fatty acid precursor, alpha-linolenic acid (ALA, 18:3n-3). Chronic RISP treatment resulted in therapeutically-relevant plasma RISP and 9-OH-RISP concentrations (18+/-2.6 ng/ml), and significantly increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3, +22%, p=0.0003) and docosapentaenoic acid (22:5n-3, +18%, p=0.01) composition, and increased PFC DHA composition (+7%, p=0.03) in rats maintained on the ALA+ diet. In contrast, chronic RISP did not alter erythrocyte or PFC omega-3 fatty acid composition in rats maintained on the ALA- diet. Chronic RISP treatment did not alter erythrocyte or PFC arachidonic acid (AA, 20:4n-6) composition. These data suggest that chronic RISP treatment significantly augments ALA-DHA biosynthesis, and preferentially increases peripheral and central membrane omega-3 fatty acid composition. Augmented omega-3 fatty acid biosynthesis and membrane composition represents a novel mechanism of action that may contribute in part to the efficacy of RISP in the treatment of SZ.

Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: dissociation from estrogenic effects.

A dysregulation in central serotonin neurotransmission and omega-3 fatty acid deficiency have been implicated in the pathophysiology of major depression. To determine the effects of omega-3 fatty acid deficiency on indices of serotonin neurotransmission in the adult rat brain, female rats were fed diets with or without the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during perinatal (E0-P90), post-weaning (P21-P90), and post-pubescent (P60-130) development. Ovariectomized (OVX) rats and OVX rats with cyclic estrogen treatment were also examined. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and fatty acid composition were determined in the prefrontal cortex (PFC), and tryptophan hydroxylase-2 (TPH-2), serotonin transporter, and 5-HT(1A) autoreceptor mRNA expression were determined in the midbrain. ALA deficiency during perinatal (-62%, p=0.0001), post-weaning (-34%, p=0.0001), and post-pubertal (-10%, p=0.0001) development resulted in a graded reduction in adult PFC docosahexaenoic acid (DHA, 22:6n-3) composition. Relative to controls, perinatal DHA-deficient rats exhibited significantly lower PFC 5-HT content (-65%, p=0.001), significant greater 5-HIAA content (+15%, p=0.046), and a significant greater 5-HIAA/5-HT ratio (+73%, p=0.001). Conversely, post-weaning DHA-deficient rats exhibited significantly greater PFC 5-HT content (+12%, p=0.03), no change in 5-HIAA content, and a significantly smaller 5-HIAA/5-HT ratio (-9%, p=0.01). Post-pubertal DHA-deficient and OXV rats did not exhibit significant alterations in PFC 5-HT or 5-HIAA content. Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (-29%, p=0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen.

Fatty acid composition of the postmortem prefrontal cortex of adolescent male and female suicide victims.

Prior epidemiological, prospective intervention, and peripheral and central fatty acid composition studies suggest that omega-3 fatty acid deficiency may be associated with the pathoaetiology of depression and suicide. In the present study, we determined the fatty acid composition of the postmortem prefrontal cortex (PFC) of adolescent male and female suicide victims and age-matched controls. Fatty acid composition (wt% total fatty acids) and concentrations (micromol/g) were determined in the postmortem PFC (Brodmann area 10) of male and female adolescent (aged 13-20 years) suicide victims (n=20) and age-matched controls (n=20) by gas chromatography. None of the major polyunsaturated fatty acids including the principle brain omega-3 fatty acid, docosahexaenoic acid (DHA), monounsaturated fatty acids, or saturated fatty acids differed significantly between adolescent suicide victims and controls before or after segregation by gender. The arachidonic acid (AA, 20:4n-6): DHA ratio and adrenic acid (22:4n-6) composition were negatively correlated with age at death in controls but not in suicides, and males exhibited a greater AA:DHA ratio irrespective of cause-of-death. These results demonstrate that adolescent male and female suicide victims do not exhibit DHA deficits in the postmortem PFC relative to age-matched controls, and suggest that suicide victims do not exhibit the normal age-related decrease in adrenic acid composition and the AA:DHA ratio.