Polyunsaturated Fatty Acids Regulate Glucose And Lipid Homeostasis In Obesity Through Adipose-Gut-Liver Axis

Polyunsaturated fatty acid(PUFA),which exists in many fatty foods,especially vegetable oils and fish,has become the focus of research in functional foods because of its important physiological functions.Although some studies have suggested PUFAs had protective effects on obesity-related metabolic diseases,including cardiovascular disease(CVD)and type 2 diabetes(T2D),findings from epidemiological studies appeared inconclusive and evidence from large-scale population-based studies is lacking.In addition,recent studies have shown that gut microbes are closely related to obesity and the complex interactions between gut,adipose and liver play a critical role in the development of obesity-related metabolic diseases.However,the mechanism regarding the effects of PUFAs on glucose and lipid metabolism remains unclear.There is a lack of in-depth research on specific types of omega-6 and omega-3 PUFAs.To clarify the relationship between PUFAs and obesity-related metabolic diseases and elucidate the underlying mechanism on regulating glucose and lipid metabolism in the context of obesity,this study assessed the associations of dietary PUFAs with risk of obesity-related metabolic diseases in large prospective cohorts in China and the United States.Furthermore,studies using animal models were conducted to explore the differential effects of PUFAs,including linoleic acid(LA),arachidonic acid(AA),?-linolenic acid(ALA),eicosapentaenoic acid(EPA)and docosahexaenoic acid(DHA),on gut microbiota and the mechanism of action on regulating glucose and lipid homeostasis through the adipose-gut-liver axis.The main results of this study are as follows:(1)In large prospective cohort studies,dietary PUFAs consumption was inversely associated with CVD and chronic liver disease mortality.Intake of omega-3 PUFA lowered the risk of CVD and chronic liver disease mortality.LA intake reduced the risk of death from CVD and diabetes whereas AA intake correlated with higher CVD mortality.ALA consumption was associated with decreased risk of T2 D,whereas LA intake was related to reduced risk of T2 D in obese women.The cross-sectional analysis showed an inverse relationship between plasma DHA level and body fat percentage.(2)In mouse study,C57BL/6J mice were fed a high fat diet to introduce obesity(DIO)and then received a diet enriched with LA,ALA,AA,EPA or DHA for 15 weeks.Results showed that ALA and LA improved the gut microbiota composition in male and female mice,respectively,which relieved endotoxemia and adipose inflammation.Therefore,insulin signaling and GLUT4 translocation were then promoted and glucose metabolism was improved.(3)AA administration aggravated the obesity phenotype and inhibited white adipose adipose browning and energy expenditure in DIO mice.In male mice,AA elevated the abundance of inflammatory gut microbial species,reduced butyrate and serotonin production,triggered systemic inflammation,exacerbated fatty liver and insulin resistance.In female mice,AA favored anti-inflammatory and butyrate-producing species,alleviated fatty liver,adipose inflammation and insulin resistance.(4)EPA and DHA feeding promoted browning of white adipose and energy expenditure in DIO mice.DHA decreased subcutaneous fat accumulation and exhibited a better capability of inducing browning of white adipose.EPA and DHA intervention enriched the abundance of Lactobacillus and short-chain fatty acids(SCFA)producing species while reduced lipopolysaccharide(LPS)-producing Bilophila and Escherichia/Shigella.The shifts in gut microbiome co-occurred with the changes in levels of propionic/butyric acid,circulating LPS and serotonin,which relieved adipose inflammation and improved glucose metabolism.(5)C57BL/KsJ-db/db mice were fed a diet enriched with EPA or DHA for 10 weeks.Supplementation of DHA and EPA attenuated hyperglycemia and insulin resistance without affecting body weight in db/db mice while the ameliorative effect appeared to be more pronounced for EPA.DHA/EPA supplementation reduced the abundance of the LPS-producing Enterobacteriaceae whereas elevated the family Coriobacteriaceae negatively correlated with glutamate level,genera Barnesiella and Clostridium XlVa associated with bile acids production,beneficial Bifidobacterium and Lactobacillus,and SCFA-producing species.The gut microbiome alterations co-occurred with the shifts in metabolome,including glutamate,bile acids,propionic/butyric acid and LPS,which subsequently relieved ?-cell apoptosis,suppressed hepatic gluconeogenesis and promoted white adipose beiging and insulin signaling.All these changes appeared to be more evident for EPA.Furthermore,transplantation with DHA/EPA-mediated gut microbiota mimicked the ameliorative effect of DHA/EPA on glucose homeostasis in db/db mice,together with similar changes in gut metabolites.In conclusion,the current study demonstrates different types of dietary PUFAs have divergent associations with obesity-related metabolic diseases and then reveals that PUFAs manipulate glucose and lipid homeostasis through adipose-gut-liver axis in DIO mice.Findings from this work will deepen the scientific understanding of different types of PUFAs on the regulation of glucose and lipid metabolism in obesity,provide strong scientific evidence for improving dietary recommendations on dietary fats and develop new directions and ideas for the research on dietary nutrients in the prevention and treatment of obesity-related metabolic diseases.