BackgroundUnderstanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS.ResultsHere we show that gut microbiome mediates the preventive effect of estrogen (17β-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17β-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17β-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17β-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters.ConclusionsIn summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0587-0) contains supplementary material, which is available to authorized users.

Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial flora. This review examines the effects the “Western”, “plant-based”, “high-fat”, “medical ketogenic”, and “Mediterranean” diets have on the composition of the gut microbiota in both mice and human subjects. We show that specific dietary components that are commonly found in the “plant-based” and “Mediterranean” diet play a role in shifting the microbial composition. This review further evaluates the bacterial metabolites that are associated with diet, and their role in systemic inflammation and metabolic endotoxemia. Furthermore, the associations between diet/dietary components and altering bacterial composition, may lead to potential therapeutic targets for type II diabetes, obesity, and inflammatory diseases.

An unbalanced increase in dietary omega-6 (n-6) polyunsaturated fatty acids (PUFA) and decrease in omega-3 (n-3) PUFA in the Western diet coincides with the global rise in chronic diseases. Whether n-6 and n-3 PUFA oppositely contribute to the development of chronic disease remains controversial. By using transgenic mice capable of synthesizing PUFA to eliminate confounding factors of diet, we show here that alteration of the tissue n-6/n-3 PUFA ratio leads to correlated changes in the gut microbiome and fecal and serum metabolites. Transgenic mice able to overproduce n-6 PUFA and achieve a high tissue n-6/n-3 PUFA ratio exhibit an increased risk for metabolic diseases and cancer, whereas mice able to convert n-6 to n-3 PUFA, and that have a lower n-6/n-3 ratio, show healthy phenotypes. Our study demonstrates that n-6 PUFA may be harmful in excess and suggests the importance of a low tissue n-6/n-3 ratio in reducing the risk for chronic diseases.

Background Avocados are a nutrient-dense source of MUFAs and are rich in antioxidants. Avocados have an additional LDL cholesterol (LDL-C) lowering effect beyond that observed when their MUFAs are substituted for SFAs, especially on small, dense LDL (sdLDL) particles, which are susceptible to in vivo oxidation and associated with increased risk of cardiovascular disease (CVD). Objectives We investigated whether a healthy diet with 1 avocado daily decreased the following secondary outcomes: circulating oxidized LDL (oxLDL) and related oxidative stress markers. Methods A randomized, crossover, controlled feeding trial was conducted with 45 men and women, aged 21–70 y, with overweight or obesity and elevated LDL-C (25th–90th percentile). Three cholesterol-lowering diets were provided (5 wk each) in random sequences: a lower-fat (LF) diet (24% calories from fat—7% SFAs, 11% MUFAs, 6% PUFAs) and 2 moderate-fat (MF) diets (34% calories from fat—6% SFAs, 17% MUFAs, 9% PUFAs): the avocado (AV) diet included 1 Hass avocado (∼136 g) per day, and the MF diet used high oleic acid oils to match the fatty acid profile of 1 avocado. A general linear mixed model was used to analyze the treatment effects. Results Compared with baseline, the AV diet significantly decreased circulating oxLDL (−7.0 U/L, –8.8%, P = 0.0004) and increased plasma lutein concentration (19.6 nmol/L, 68.7%, P < 0.0001), and both changes differed significantly from that after the MF and LF diets (P ≤ 0.05). The change in oxLDL caused by the AV diet was significantly correlated with the changes in the number of sdLDL particles (r = 0.32, P = 0.0002) but not large, buoyant LDL particles. Conclusions One avocado a day in a heart-healthy diet decreased oxLDL in adults with overweight and obesity, and the effect was associated with the reduction in sdLDL. This trial was registered at http://www.clinicaltrials.gov as NCT01235832.

Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution.

Iron deficiency anemia in early life alters the development and functioning of the dopamine neurotransmitter system, but data regarding the specific effects of brain iron loss on dopamine D(2) receptor regulation are lacking. Cell culture and animal models were employed in this study to determine whether D(2) receptor expression is altered when cellular iron levels are depleted. Endogenous D(2) receptor-expressing PC12 cells exposed to increasing concentrations of the iron chelator desferrioxamine (25-100 micromol/L) exhibited dose-dependent decreases in total D(2) receptor protein concentrations (20-65%), but there were minimal effects on D(2) receptor mRNA levels. When iron-deficient cells were repleted with ferric ammonium citrate for 24 h, D(2) receptor protein densities were similar to control. Dietary iron deficiency for 6 wk in weanling rats also reduced regional iron concentrations by nearly 50% in the ventral midbrain and caudate but did not affect D(2) receptor mRNA levels in the ventral midbrain. Iron deficiency significantly reduced membrane D(2) receptor protein levels by >70% in caudate, whereas cytosolic concentrations showed only 25% losses. D(2) receptor protein densities and regional iron concentrations were restored within 2 wk of dietary iron repletion. These results support the concept that D(2) receptor gene expression is not significantly changed by iron deficiency, whereas dopamine receptor trafficking is affected and is likely related to known dopamine system alterations in iron deficiency.

Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere-derived MCF-7 cells and HMLE-Twist-ER cells, we found that the cells with stem cell-like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl-CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega-6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self-renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self-renewal and growth. Dietary supplementation of nude mice bearing BCSC-derived tumors with omega-3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self-renewal and growth of BCSC, and that omega-3 fatty acids are effective in targeting this pathway to exert their anticancer effect.

Objective Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions. Material/Methods PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3. Results In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells. Conclusions Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line.