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

Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0516, United States.
Psychoneuroendocrinology (Impact Factor: 5.59). 12/2008; 34(4):532-9. DOI: 10.1016/j.psyneuen.2008.10.013
Source: PubMed

ABSTRACT 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.

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Available from: Ronald Jandacek, Jun 27, 2014
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    • "Preclinical evidence further suggests that chronic treatment with SGA medications increases rat erythrocyte and heart EPA + DHA composition by augmenting biosynthesis [36] [37]. Furthermore, preclinical and clinical evidence suggests that ovarian hormones augment LCn − 3 fatty acid biosynthesis and erythrocyte DHA composition [38] [39] [40] [41], and that erythrocyte [31] and postmortem brain [35] DHA deficits are more robust in male than female SZ patients. The primary objective of the present study was to compare erythrocyte EPA + DHA composition in adult medication-free male and female SZ patients and healthy controls. "
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    ABSTRACT: Deficiency in long-chain omega-3 (LCn - 3) fatty acids, eicosapentaenoic acid (EPA, 20:5n - 3) and docosahexaenoic acid (DHA, 22:6n - 3), has been implicated in the pathoetiology of cardiovascular disease, a primary cause of excess premature mortality in patients with schizophrenia (SZ). In the present study, we determined erythrocyte EPA + DHA levels in adult medication-free patients SZ (n = 20) and age-matched healthy controls (n = 24). Erythrocyte EPA + DHA composition exhibited by SZ patients (3.5%) was significantly lower than healthy controls (4.5%, -22%, P = 0.007). The majority of SZ patients (72%) exhibited EPA+DHA levels ≤4.0% compared with 37% of controls (Chi-square, P = 0.001). In contrast, the omega-6 fatty acid arachidonic acid (AA, 20:4n - 6) (+9%, P = 0.02) and the AA:EPA + DHA ratio (+28%, P = 0.0004) were significantly greater in SZ patients. Linoleic acid (18:2n - 6) was significantly lower (-12%, P = 0.009) and the erythrocyte 20:3/18:2 ratio (an index of delta6-desaturase activity) was significantly elevated in SZ patients. Compared with same-gender controls, EPA + DHA composition was significantly lower in male (-19%, P = 0.04) but not female (-13%, P = 0.33) SZ patients, whereas the 20:3/18:2 ratio was significantly elevated in both male (+22%, P = 0.008) and female (+22%, P = 0.04) SZ patients. These results suggest that the majority of SZ patients exhibit low LCn - 3 fatty acid levels which may place them at increased risk for cardiovascular morbidity and mortality.
    Cardiovascular Psychiatry and Neurology 02/2013; 2013:796462. DOI:10.1155/2013/796462
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    • "This finding is consistent with previous work showing a lack of sex difference in cerebral cortex phospholipid DHA levels (Extier et al. 2010). One study showed higher prefrontal cortex total lipid DHA levels in males (McNamara et al. 2009), suggesting that sex differences in brain DHA content are specific to the brain area investigated. Brain DHA levels are quite stable throughout the lifetime of rats after weaning, as DHA-free artificial rearing (Lim et al. 2005; Ward et al. 1996) or multigenerational dietary DHA deficiency (Bourre et al. 1984) is required to reduce rat brain DHA stores. "
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    ABSTRACT: Docosahexaenoic acid (DHA, 22:6n-3) is higher in the blood and tissues of females relative to males, but the underlying mechanism is not clear. The present study examined the expression of enzymes involved in the biosynthesis of DHA from short-chain n-3 polyunsaturated fatty acids in male and female rats (n = 6 for each sex). Rats were maintained on an AIN-93G diet and sacrificed at 14 weeks of age after an overnight fast. Plasma, erythrocytes, liver, heart, and brain were collected for fatty acid composition analysis and the determination of enzyme and transcription factor expression by RT-PCR and immunoblotting. Females had higher DHA concentrations in the total lipids of liver, plasma, erythrocyte, and heart (53%, 75%, 36%, and 25% higher, respectively, compared with males) with no sex differences in brain DHA concentrations. The mRNA content of Δ5-desaturase, Δ6-desaturase, and elongase 2 was 1.0-, 1.4-, and 1.1-fold higher, respectively, in the livers of female rats compared with males, with no differences in the hearts or brains. The protein content of Δ6-desaturase was also higher in females. Higher hepatic mRNA of sterol-regulatory element-binding protein 1-c and estrogen receptor α in the females suggests that lipogenic and estrogen signaling mechanisms are involved. The sex difference in DHA concentration is tissue specific and is associated with higher Δ6-desaturase expression in females relative to males, which appears to be limited to the liver.
    Applied Physiology Nutrition and Metabolism 10/2012; 37(6). DOI:10.1139/h2012-103 · 2.23 Impact Factor
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    • "Second, only male rats were employed, precluding evaluation of potential gender differences. However, male rats were selected to obviate potential interactions with ovarian hormones previously found to influence the biosynthesis of PUFAs (Childs et al., 2010; McNamara et al., 2009b), which regulate Scd1 expression/activity (Landschulz et al., 1994; Ntambi, 1999; Sessler et al., 1996), and TG synthesis (Hassanali et al., 2010; Lu et al., 2011; Mustad et al., 2006). Third, we did not directly evaluate Scd1 enzyme activity, and used the plasma 18:1/18:0 ratio as a surrogate measure. "
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    ABSTRACT: Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, and 6mg/kg/d), paliperidone (1.5, 3, and 6mg/kg/d), olanzapine (2.5, 5, and 10mg/kg/d), quetiapine (5, 10, and 20mg/kg/d), haloperidol (1, and 3mg/kg/d) or vehicle through their drinking water for 40days. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, 'desaturation index') were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG and glucose levels, and that concomitant elevations in PUFA biosynthesis oppose these effects.
    Schizophrenia Research 06/2011; 129(1):66-73. DOI:10.1016/j.schres.2011.03.016 · 4.43 Impact Factor
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