👤 Ronald Jandacek

This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids. Show less

Polyunsaturated fatty acids (PUFA), a lipid family comprised of omega-3 (n-3) and n-6 fatty acids, are a critical component of cellular membranes, and recent in vitro studies have found that antipsychotic medications up-regulate genes responsible for PUFA biosynthesis. To evaluate this effect in vivo, rats were treated with risperidone (1.5, 3, 6mg/kg/day), paliperidone (1.5, 3, 6mg/kg/day), olanzapine (2.5, 5, 10mg/kg/day), quetiapine (5, 10, 20mg/kg/day), haloperidol (1, 3mg/kg/day) or vehicle through their drinking water for 40day. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n-3 (plasma 22:6/18:3 and 20:5/18:3 ratios) and n-6 (plasma 20:4/18:2 and 20:3/18:2 ratios) biosynthesis, and peripheral (erythrocyte, heart) and central (frontal cortex) membrane PUFA composition were determined. Only risperidone and its metabolite paliperidone significantly and selectively up-regulated liver delta-6 desaturase (Fads2) mRNA expression, and robustly increased plasma indices of n-3 and n-6 fatty acid biosynthesis. In risperidone- and paliperidone-treated rats, plasma indices of n-3 and n-6 fatty acid biosynthesis were all positively correlated with liver Fads2 mRNA expression, but not Fads1, Elovl2, or Elovl5 mRNA expression. All antipsychotics at specific doses increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition, and all except quetiapine increased arachidonic acid (AA, 20:4n-6) composition. Risperidone, paliperidone, and olanzapine increased heart DHA and AA composition, and no antipsychotic altered frontal cortex DHA or AA composition. These in vivo data demonstrate that augmentation of PUFA biosynthesis is not common to all antipsychotic medications, and that risperidone and paliperidone uniquely increase delta-6 desaturase (Fads2) mRNA expression and most robustly increase PUFA biosynthesis and peripheral membrane composition. Show less

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. Show less

To further investigate the role of intestinal aplipoprotein A-IV (apo A-IV) in the management of daily food intake, we examined the diurnal patterns in apo A-IV gene and protein expression in freely feeding (FF) and food-restricted (FR; food provided 4 h daily for 4 wk) rats that were killed at 3-h intervals throughout the 24-h diurnal cycle. In FF rats, the intestinal apo A-IV mRNA and protein levels showed a circadian rhythm concomitant with the feeding pattern. The daily pattern of fluctuation of apo A-IV, however, was altered in FR rats, which had a marked increase in intestinal apo A-IV levels during the 4-h feeding period of light phase. In both FF and FR rats, increased plasma corticosterone (Cort) levels temporally coincided with the increasing phase of intestinal apo A-IV mRNA and protein expression. Depletion of Cort by adrenalectomy abolished the diurnal rhythm by decreasing the apo A-IV expression during the dark period but did not change the feeding rhythm. Exposure of adrenalectomized rats to consistent Cort level (50-mg continuous release Cort pellet) resulted in fixed apo A-IV levels throughout the day. These results indicate that intestinal apo A-IV exhibits a diurnal rhythm, which can be regulated by endogenous Cort independently of the light-dark cue. The fact that intestinal apo A-IV levels were consistent with the food intake during the normal diurnal cycle as well as during the cycle of 4-h feeding each day suggests that intestinal apo A-IV is involved in the regulation of daily food intake. Show less