Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

Effects of natural S-equol supplements on overweight or obesity and metabolic syndrome in the Japanese, based on sex and equol status.

OBJECTIVES: Epidemiologic studies indicate that soy intake has an important role in the prevention of age-related health problems. Daidzein, the principal isoflavone contained in soy, is converted to S-equol by the intestinal bacteria. Not all individuals, however, can produce S-equol, which is considered the most biologically active metabolite. We studied the effects of a natural S-equol supplement on metabolic parameters associated with overweight or obesity and metabolic syndrome. METHODS: The study was a randomized, double-blinded, placebo-controlled, crossover design with no washout period. All subjects were considered overweight or obese if they had a body mass index ≥ 25 kg/m(2) . Placebo or natural S-equol tablets containing 10 mg S-equol were orally ingested each day for 12 weeks. A total of 54 Japanese overweight or obese outpatients were enrolled. The equol phenotype was determined, and various metabolic parameters, including cardio-ankle vascular index (CAVI), were measured. RESULTS: Equol non-producers comprised 67.9% of the overweight or obese subjects. The ratio of equol non-producers in this overweight or obese subject group was higher than the previously reported ratio of equol non-producers (approximately 50%) in the general population. Compared with the placebo group, intervention with natural S-equol led to a significant decrease in HbA1c, serum low-density lipoprotein cholesterol (LDL-C) levels and CAVI score. Furthermore, the effect was more prominent in the subgroup of female equol non-producers. CONCLUSION: The ratio of equol non-producers in overweight or obese populations might be higher than generally reported. Natural S-equol might have a role in glycaemic control and in the prevention of cardiovascular disease by its effects to lower LDL-C levels and CAVI scores in overweight or obese individuals.