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Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well-established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob; LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P < 0.01), triglycerides (P< 0.01), and free fatty acids (P< 0.001) in lean LDLR-/- mice, but not in ob/ob; LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob; LDLR-/- mice (P < 0.05) compared with olive oil fed ob/ob; LDLR-/- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P < 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob; LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice. J. Nutr. 139: 2380-2386, 2009. Manuscript received June 12, 2009. Initial review completed July 17, 2009. Revision accepted October 15, 2009. First published online October 28, 2009; doi: 10.3945/jn.109.111567.

A high-NaCl diet induces renal medullary cyclooxygenase (COX)2 expression, and selective intramedullary infusion of a COX2 inhibitor increases blood pressure in rats on a high-salt diet. The present study characterized the specific prostanoid contributing to the antihypertensire effect of COX2. C57BL/6J mice placed on a high-NaCl diet exhibited increased medullary COX2 and microsomal prostaglandin E synthasel (mPGES1) expression as determined by immunoblot and real-time PCR. Cytosolic prostaglandin E synthase and prostacyclin synthase were not induced by the high-salt diet. Immunofluorescence showed mPGES1 in collecting ducts and interstitial cells. High salt increased renal medullary [PGE.sub.2] as determined by gas chromatography/negative ion chemical ionization mass spectrometry. The effect of direct intramedullary [PGE.sub.2] infusion was examined in anesthetized uninephrectomized mice. Intramedullary [PGE.sub.2] infusion (10 ng/h) increased urine volume (from 3.3 [+ or -] 0.6 to 9.5 [+ or -] 1.6 [micro]l/min) and urine sodium excretion (0.11 [+ or -] 0.02 to 0.32 [+ or -] 0.05 [micro]eq/min). To determine which E-prostanoid (EP) receptor(s) mediated [PGE.sub.2]-dependent natriuresis, EP-selective prostanoids were infused. The [EP.sub.2] agonist butaprost produced natriuresis (from 0.06 [+ or -] 0.02 to 0.32 [+ or -] 0.05 [micro]eq/min). The natriuretic effect of intramedullary [PGE.sub.2] or butaprost was abolished in EP2-deficient mice, which exhibit NaCl-dependent hypertension. In conclusion, a high-salt diet increases renal medullary COX2 and mPGES1 expression, and increases renal medullary [PGE.sub.2] synthesis. Renal medullary [PGE.sub.2] promotes renal sodium excretion via the EP2 receptor, thereby maintaining normotension in the setting of high salt intake. cyclooxygenase 2; prostaglandin E synthase; hypertension

Cytosolic phospholipase [A.sub.2[alpha]] ([cPLA.sub.2[alpha]]) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of [cPLA.sub.2[alpha]] function has been derived from investigations of the enzyme and from [cPLA.sub.2[alpha]]-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane [B.sub.2] and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene [B.sub.4] released from calcium ionophore--activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient&apos;s [cPLA.sub.2[alpha]] genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total [PLA.sub.2] activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin [E.sub.2], prostaglandin [D.sub.2], and thromboxane [A.sub.2] were also reduced. These findings characterize what we believe is a novel inherited deficiency of [cPLA.sub.2]., Introduction These investigations addressed the problem of a patient with multiple small intestinal ulcers that were not associated with use of NSAIDs. The patient had chronic gastrointestinal blood loss from [...]

Although fish oil has hypolipidemic and antiatherosclerotic properties, the potential for white adipose tissue (WAT) to mediate these effects has not been studied. LDL-receptor deficient (LDLR-/-) mice were fed high fat, olive oil-containing diets supplemented with additional olive oil or with fish oil for 12 wk. Fish oil feeding significantly reduced plasma lipid levels. In contrast, lipid storage in WAT was increased in fish oil-fed mice as evidenced by increased total fat (P < 0.05) and perigonadal WAT mass (P < 0.05), increased cholesterol storage (P < 0.001), and adipocyte hypertrophy. Despite increased adipose tissue mass, WAT-specific inflammation and insulin sensitivity were improved (P < 0.05), concomitant with reduced macrophage infiltration. Furthermore, fish oil increased WAT and plasma levels of adiponectin. In addition, fish oil feeding decreased the formation of proinflammatory F2- isoprostanes, markers of oxidative stress (P < 0.05). The increased WAT lipid storage in fish oil-fed mice was associated with reduced lipid accumulation in liver (P < 0.05) and decreased atherosclerotic lesion area (P < 0.05). Taken together, these data highlight the specific role of WAT in regulating dietary fish oil-mediated improvement in systemic lipid homeostasis and atherosclerosis.