Vascular Dysfunction Induced in Offspring by Maternal Dietary Fat Involves Altered Arterial Polyunsaturated Fatty Acid Biosynthesis

Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG −394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis

Impaired Fluid Intake, but Not Sodium Appetite, in Aged Rats Is Mediated by the Cyclooxygenase-Prostaglandin E<inf>2</inf> Pathway

Aging results in decreased fluid intake following dehydration and other dipsogenic stimuli; similar reductions in sodium intake have also been observed with aging. Given that cyclooxygenase (COX)-derived prostanoids are elevated in aged rats in the midbrain and proinflammatory prostanoids are known to decrease fluid intake in dehydrated rats, the aim of this study was to determine if the reductions of fluid intake and sodium intake in aging are mediated by proinflammatory eicosanoid signaling. Therefore, we examined the effect of acute COX inhibition in adult (4 months-old) and aged (30 months-old) rats prior to ingestive behavior challenges. COX inhibition, using acetylsalicylic acid (ASA), increased fluid intake in aged, but not adult, rats in response to 24-h dehydration. ASA had no effect on salt intake following sodium depletion and ASA did not change basal fluid or sodium consumption in either age group. Hypothalamic COX-1 and -2, prostaglandin E synthase (PGES) and inducible nitric oxide synthase (iNOS) mRNA expression were all elevated in aged animals, leading to elevated PGE2 levels. COX expression in the hypothalamus was reduced by ASA treatment in rats of both ages resulting in reduced PGE2 levels in aged ASA treated animals. These data indicate that the reduced fluid intake that occurs in aging is due to increased COX-PGE2-mediated inflammation. However, the reduced sodium intake in these animals appears to occur via an alternate mechanism

1-Sarcosine-angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model

BACKGROUND: There are a myriad of proteins responsible for modulation of expenditure of energy. Angiotensin II (Ang II) is a vital component of renin-angiotensin system that affects blood pressure and also linked to both cachexia and obesity via fat and muscle metabolism. Previous research suggests that the direct action of Ang II is on the brain, via angiotensin II type 1 receptor protein, affecting food intake and energy expenditure. The objective of the study is to investigate the effect of 1-sarcosine (SAR)-Ang II infusion on energy expenditure and metabolism in a rat model of congestive heart failure cachexia. METHODS: Adult female rats of the Sprague Dawley strain (n = 33) were used (11 pair-fed control, 12 ad libitum and 10, 1-sarcosine-angiotensin II-infused rats). Body weight, faecal excretion, feed intake (in grams), water intake (in milliliters) and urine excreted were recorded daily. The measurements were recorded in three different periods (4 days prior to surgery, "pre-infusion"; day of surgery and 5 days postsurgery, "infusion period"; days 7 to 14, "recovery" period). Different analytical methods were used to measure energy expenditure per period, uncoupling protein 3 mRNA expression, crude protein and adipose tissue body composition. RESULTS: During the infusion period, the SAR-Ang II group experienced rapid weight loss (p < 0.05) in comparison to the ad libitum and pair-fed groups. The SAR-Ang II group displayed lower (p < 0.05) body fat content (in percent) than the controls. There was also increased (p < 0.05) uncoupling protein 3 (UCP3) mRNA expression in the SAR-Ang II group and pair-fed group when compared to the controls. CONCLUSION: In summary, the results suggest that SAR-Ang II infusion impairs appetite and decreases body weight by wasting predominantly adipose tissue, which may be due to elevated energy expenditure via mitochondrial uncoupling (UCP3 protein activity)

Dietary repletion with ω3 fatty acid or with COX inhibition reverses cognitive effects in F3 ω3 fatty-acid-deficient mice

Dietary deficiency of &omega;3 fatty acid during development leads to impaired cognitive function. However, the effects of multiple generations of &omega;3 fatty-acid deficiency on cognitive impairment remain unclear. In addition, we sought to test the hypothesis that the cognitive impairments of &omega;3 fatty-acid-deficient mice are mediated through the arachidonic acid-cyclooxygenase (COX) pathway. To address these issues, C57BL/6J mice were bred for 3 generations and fed diets either deficient (DEF) or sufficient (SUF) in &omega;3 fatty acids. At postnatal day 21, the F3 offspring remained on the dam\u27s diet or were switched to the opposite diet, creating 4 groups. In addition, 2 groups that remained on the dam\u27s diet were treated with a COX inhibitor. At 19 wk of age, spatial-recognition memory was tested on a Y-maze. Results showed that 16 wk of SUF diet reversed the cognitive impairment of F3 DEF mice. However, 16 wk of &omega;3 fatty-acid-deficient diet impaired the cognitive performance of the F3 SUF mice, which did not differ from that of the F3 DEF mice. These findings suggest that the cognitive deficits after multigenerational maintenance on &omega;3 fatty-acid-deficient diet are not any greater than are those after deficiency during a single generation. In addition, treatment with a COX inhibitor prevented spatial-recognition deficits in F3 DEF mice. Therefore, cognitive impairment due to dietary &omega;3 fatty-acid deficiency appears to be mediated by the arachidonic acid-COX pathway and can be prevented by 16 wk of dietary repletion with &omega;3 fatty acids or COX inhibition

Localisation of 11β‐Hydroxysteroid Dehydrogenase Type 2 in Mineralocorticoid Receptor Expressing Magnocellular Neurosecretory Neurones of the Rat Supraoptic and Paraventricular Nuclei

An accumulating body of evidence suggests that the activity of the mineralocorticoid, aldosterone, in the brain via the mineralocorticoid receptor (MR) plays an important role in the regulation of blood pressure. MR was recently found in vasopressin and oxytocin synthesising magnocellular neurosecretory cells (MNCs) in both the paraventricular (PVN) and supraoptic (SON) nuclei in the hypothalamus. Considering the physiological effects of these hormones, MR in these neurones may be an important site mediating the action of aldosterone in blood pressure regulation within the brain. However, aldosterone activation of MR in the hypothalamus remains controversial as a result of the high binding affinity of glucocorticoids to MR at substantially higher concentrations compared to aldosterone. In aldosterone‐sensitive epithelia, the enzyme 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2) prevents glucocorticoids from binding to MR by converting glucocorticoids into inactive metabolites. The present study aimed to determine whether 11β‐HSD2, which increases aldosterone selectivity, is expressed in MNCs. Specific 11β‐HSD2 immunoreactivity was found in the cytoplasm of the MNCs in both the SON and PVN. In addition, double‐fluorescence confocal microscopy demonstrated that MR‐immunoreactivity and 11β‐HSD2‐in situ hybridised products are colocalised in MNCs. Lastly, single‐cell reverse transcriptase‐polymerase chain reaction detected MR and 11β‐HSD2 mRNAs from cDNA libraries derived from single identified MNCs. These findings strongly suggest that MNCs in the SON and PVN are aldosterone‐sensitive neurones