Omega-3 Polyunsaturated Fatty Acids Protect against High-Fat Diet-Induced Morphological and Functional Impairments of Brown Fat in Transgenic Fat-1 Mice.

The role of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the regulation of energy homeostasis remains poorly understood. In this study, we used a transgenic fat-1 mouse model, which can produce n-3 PUFAs endogenously, to investigate how n-3 PUFAs regulate the morphology and function of brown adipose tissue (BAT). We found that high-fat diet (HFD) induced a remarkable morphological change in BAT, characterized by "whitening" due to large lipid droplet accumulation within BAT cells, associated with obesity in wild-type (WT) mice, whereas the changes in body fat mass and BAT morphology were significantly alleviated in fat-1 mice. The expression of thermogenic markers and lypolytic enzymes was significantly higher in fat-1 mice than that in WT mice fed with HFD. In addition, fat-1 mice had significantly lower levels of inflammatory markers in BAT and lipopolysaccharide (LPS) in plasma compared with WT mice. Furthermore, fat-1 mice were resistant to LPS-induced suppression of UCP1 and PGC-1 expression and lipid deposits in BAT. Our data has demonstrated that high-fat diet-induced obesity is associated with impairments of BAT morphology (whitening) and function, which can be ameliorated by elevated tissue status of n-3 PUFAs, possibly through suppressing the effects of LPS on inflammation and thermogenesis.

Decreased Tissue Omega-6/Omega-3 Fatty Acid Ratio Prevents Chemotherapy-Induced Gastrointestinal Toxicity Associated with Alterations of Gut Microbiome.

Gastrointestinal toxicity (GIT) is a debilitating side effect of Irinotecan (CPT-11) and limits its clinical utility. Gut dysbiosis has been shown to mediate this side effect of CPT-11 by increasing gut bacterial ß-glucuronidase (GUSB) activity and impairing the intestinal mucosal barrier (IMB). We have recently shown the opposing effects of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) on the gut microbiome. We hypothesized that elevated levels of tissue n-3 PUFA with a decreased n-6/n-3 PUFA ratio would reduce CPT-11-induced GIT and associated changes in the gut microbiome. Using a unique transgenic mouse (FAT-1) model combined with dietary supplementation experiments, we demonstrate that an elevated tissue n-3 PUFA status with a decreased n-6/n-3 PUFA ratio significantly reduces CPT-11-induced weight loss, bloody diarrhea, gut pathological changes, and mortality. Gut microbiome analysis by 16S rRNA gene sequencing and QIIME2 revealed that improvements in GIT were associated with the reduction in the CPT-11-induced increase in both GUSB-producing bacteria (e.g., Enterobacteriaceae) and GUSB enzyme activity, decrease in IMB-maintaining bacteria (e.g., Bifidobacterium), IMB dysfunction and systemic endotoxemia. These results uncover a host-microbiome interaction approach to the management of drug-induced gut toxicity. The prevention of CPT-11-induced gut microbiome changes by decreasing the tissue n-6/n-3 PUFA ratio could be a novel strategy to prevent chemotherapy-induced GIT.

Fish consumption, long-chain omega-3 fatty acids intake and risk of stroke: An updated systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Although fish consumption or omega-3 intake is associated with cardio- cerebrovascular disease including stroke, their correlation is still controversial. Therefore, this meta-analysis is to identify the relationship between the risk of stroke and fish consumption or omega-3 intake. METHODS AND STUDY DESIGN: We searched the PubMed, EMBASE and Cochrane Library databases as of May 2019. Multivariateadjusted risk ratios (RRs) with 95% confidence interval (CI) for stroke in different level intake of fish or Longchain omega-3 polyunsaturated fatty acids (LC ω3-PUFAs) were pooled using a random-effects meta-analysis. A dose-response analysis was conducted with the 2-stage generalized least-squares trend program. RESULTS: Our meta-analysis identified a total of 17 prospective cohort studies including 14986 strokes events in 672711 individuals. Meta-analysis revealed that the higher fish consumption was significantly associated with lower risk of stroke (RR=0.871, 95% CI: 0.779-0.975, p=0.016), especially with ischemic stroke (RR=0.808, 95% CI: 0.696- 0.937, p=0.005). Meantime, the combined RR of total stroke was 0.859 (95% CI: 0.769-0.959, p=0.007) for the highest versus lowest intake of LC ω3-PUFAs, and stratification analysis showed that higher LC ω3-PUFAs intake was associated with reduced stroke risk in women (RR=0.793, 95% CI: 0.706-0.891, p=0.000) but not in men. In addition, the dose-response analysis showed fish consumption with 1000g per month and LC ω3-PUFAs intake with 0.5g per month was associated with 17.3% (RR=0.927, 95% CI: 0.83-0.98) and 14% (RR=0.86, 95% CI: 0.78-0.95) lower risk of stroke, respectively. CONCLUSIONS: Both fish consumption and LC ω3-PUFAs intake were negatively associated with the risk of stroke, especially in women, which suggest that increased intake of fishery products and LC ω3-PUFAs may benefit primary prevention of stroke.

Cloning and characterization of two chlorophyll A/B binding protein genes and analysis of their gene family in Camellia sinensis.

In this study, two chlorophyll A/B binding protein (CAB) genes (CsCP1 and CsCP2) in tea plant were cloned. The proteins encoded by these genes belong to the external or internal antenna proteins of PS II, respectively. They may be the targets of physiological regulation for tea leaf cell PS II because they all contain multiple functional domains and modifiable sites. The CAB gene family in the tea genome consists of 25 homologous genes. We measured the expression patterns of ten genes in the CsCP1 and CsCP2 subfamily under six different stresses. CsCP1 expression was inhibited in response to 6 kinds of stress; CsCP2 expression was slightly upregulated only after cold stress and ABA treatment. However, the expression levels of CSA016997 and CSA030476 were upregulated significantly in the six stresses. The results suggested that the 10 CAB genes may have different functions in tea leaves. Moreover, changes in the expression of the 10 genes under stress appear to be related to ABA- and MeJA-dependent signalling pathways, and their responses to MeJA treatment is faster than those to ABA. In addition, we introduced our experiences for cloning the genes in the context of complex genomes.

Multi-omic analysis in transgenic mice implicates omega-6/omega-3 fatty acid imbalance as a risk factor for chronic disease.

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.

Suppression of Postprandial Blood Glucose Fluctuations by a Low-Carbohydrate, High-Protein, and High-Omega-3 Diet via Inhibition of Gluconeogenesis.

Hyperglycemia significantly contributes to the development and progression of metabolic diseases. Managing postprandial blood glucose fluctuations is of particular importance for patients with hyperglycemia, but safe and effective means of reducing blood glucose levels are still lacking. Five diets with varying macronutrient ratios and omega-3 fatty acid amounts were tested for their blood glucose-lowering effects in male C57BL/6J mice. The diets with potent blood glucose-lowering effects were further investigated for their underlying mechanisms and their beneficial effects on hyperglycemia models. Mice given the low-carbohydrate, high-protein, and high-omega-3 (LCHP+3) diet exhibited a rapid reduction of the blood glucose levels that remained consistently low, regardless of feeding. These effects were associated with reduced amino acid gluconeogenesis, due to the inhibition of hepatic alanine transaminase (ALT). Furthermore, the LCHP+3 intervention was effective in reducing the blood glucose levels in several disease conditions, including type 1 diabetes mellitus, hormone-induced hyperglycemia, and diet-induced metabolic syndrome. Our findings identify the LCHP+3 diet as a potent blood glucose-lowering diet that suppresses postprandial blood glucose fluctuations through the inhibition of gluconeogenesis and may have great clinical utility for the management of metabolic diseases with hyperglycemia.

Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids.

BACKGROUND: Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. METHODS: We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. RESULTS: We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). CONCLUSIONS: These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. GENERAL SIGNIFICANCE: 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.

A host-microbiome interaction mediates the opposing effects of omega-6 and omega-3 fatty acids on metabolic endotoxemia.

Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co-housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today's health epidemics.

Omega-3 fatty acid intervention suppresses lipopolysaccharide-induced inflammation and weight loss in mice.

Bacterial endotoxin lipopolysaccharide (LPS)-induced sepsis is a critical medical condition, characterized by a severe systemic inflammation and rapid loss of muscle mass. Preventive and therapeutic strategies for this complex disease are still lacking. Here, we evaluated the effect of omega-3 (n-3) polyunsaturated fatty acid (PUFA) intervention on LPS-challenged mice with respect to inflammation, body weight and the expression of Toll-like receptor 4 (TLR4) pathway components. LPS administration induced a dramatic loss of body weight within two days. Treatment with n-3 PUFA not only stopped loss of body weight but also gradually reversed it back to baseline levels within one week. Accordingly, the animals treated with n-3 PUFA exhibited markedly lower levels of inflammatory cytokines or markers in plasma and tissues, as well as down-regulation of TLR4 pathway components compared to animals without n-3 PUFA treatment or those treated with omega-6 PUFA. Our data demonstrate that n-3 PUFA intervention can suppress LPS-induced inflammation and weight loss via, at least in part, down-regulation of pro-inflammatory targets of the TLR4 signaling pathway, and highlight the therapeutic potential of n-3 PUFA in the management of sepsis.