N-3 polyunsaturated fatty acids: An innovative strategy against obesity and related metabolic disorders, intestinal alteration and gut microbiota dysbiosis.

Obesity is now widely recognized to be associated with low-grade systemic inflammation. It has been shown that high-fat feeding modulates gut microbiota which strongly increased intestinal permeability leading to lipopolysaccharide absorption causing metabolic endotoxemia that triggers inflammation and metabolic disorders. N-3 polyunsaturated fatty acids (PUFAs) have been shown associated with anti-obesity properties, but results still remain heterogeneous and very few studies underlined the metabolic pathways involved. Thus, the use of Fat-1 transgenic mice allows to better understanding whether endogenous n-3 PUFAs enrichment contributes to obesity and associated metabolic disorders prevention. It specially evidence that such effects occur through modulations of gut microbiota and intestinal permeability. Then, by remodeling gut microbiota, endogenous n-3 PUFAs improve HF/HS-diet induced features of the metabolic syndrome which in turn affects host metabolism. Thus, increasing anti-obesogenic microbial species in the gut microbiota population (i.e Akkermansia) by appropriate n-3 PUFAs may represent a promising strategy to control or prevent metabolic diseases.

The Transplantation of ω3 PUFA-Altered Gut Microbiota of fat-1 Mice to Wild-Type Littermates Prevents Obesity and Associated Metabolic Disorders.

Altering the gut microbiome may be beneficial to the host and recently arose as a promising strategy to manage obesity. Here, we investigated the relative contribution of ω3 polyunsaturated fatty acid (PUFA)-mediated alterations in the microbiota to metabolic parameter changes in mice. Four groups were compared: male fat-1 transgenic mice (with constitutive production of ω3 PUFAs) and male wild-type (WT) littermates fed an obesogenic (high fat/high sucrose [HFHS]) or a control diet. Unlike WT mice, HFHS-fed fat-1 mice were protected against obesity, glucose intolerance, and hepatic steatosis. Unlike WT mice, fat-1 mice maintained a normal barrier function, resulting in a significantly lower metabolic endotoxemia. The fat-1 mice displayed greater phylogenic diversity in the cecum, and fecal microbiota transplantation from fat-1 to WT mice was able to reverse weight gain and to normalize glucose tolerance and intestinal permeability. We concluded that the ω3 PUFA-mediated alteration of gut microbiota contributed to the prevention of metabolic syndrome in fat-1 mice. It occurred independently of changes in the PUFA content of host tissues and may represent a promising strategy to prevent metabolic disease and preserve a lean phenotype.

n-3 polyunsaturated fatty acids and HER2-positive breast cancer: interest of the fat-1 transgenic mouse model over conventional dietary supplementation.

Overexpression of the tyrosine kinase receptor ErbB2/HER2/Neu, occurs in 25%-30% of invasive breast cancer (BC) with poor patient prognosis. Even if numerous studies have shown prevention of breast cancer by n-3 fatty acid intake, the experimental conditions under which n-3 fatty acids exert their protective effect have been variable from study to study, preventing unifying conclusions. Due to confounding factors, inconsistencies still remain regarding protective effects of n-3 polyunsaturated fatty acids (PUFA) on BC. When animals are fed with dietary supplementation in n-3 fatty acids (the traditional approach to modify tissue content and decrease the n-6/n-3 ratio) complex dietary interactions can occur among dietary lipids (antioxidants, vitamins…) that can modulate the activity of n-3 fatty acids. So, what are the specific roles of these n-3 PUFA in reducing breast cancer risk and particularly preventing HER2-positive breast cancer? In this review, we discuss crucial points that may account for discrepancies of results and provide a highly effective genetic approach that can eliminate confounding factors of diet for evaluating the molecular mechanisms of n-3 PUFA in HER2 signaling pathway regulation. The fat-1 transgenic mouse model is capable of converting n-6 to n-3 fatty acids leading to an increase in n-3 fatty acid content with a balanced n-6/n-3 fatty acid ratio in all tissues. The fat-1 mouse model allows well-controlled studies in HER2-positive breast cancer prevention to be performed, without the conflict of potential confounding factors of diet.

Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice.

Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25-30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipidomic analyses were performed in tumor tissues and plasma. Our results showed that tumors totally disappeared by day 15 in fat-1 mice but continued to grow in WT mice. This prevention can be related in part to significant repression of the HER2/ß-catenin signaling pathway and formation of significant levels of n-3 PUFA-derived bioactive mediators (particularly 15-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and prostaglandin E3) in the tumors of fat-1 mice compared with WT mice. All together these data demonstrate an anti-BC effect of n-3 PUFAs through, at least in part, HER2 signaling pathway downregulation, and highlight the importance of gene-diet interactions in BC.