Potential Mechanisms by Which Hydroxyeicosapentaenoic Acids Regulate Glucose Homeostasis in Obesity

Dysregulation of glucose metabolism in response to diet-induced obesity contributes toward numerous complications, such as insulin resistance and hepatic steatosis. Therefore, there is a need to develop effective strategies to improve glucose homeostasis. In this review, we first discuss emerging evidence from epidemiological studies and rodent experiments that increased consumption of EPA (either as oily fish, or dietary/pharmacological supplements) may have a role in preventing impairments in insulin and glucose homeostasis. We then review the current evidence on how EPA-derived metabolites known as hydroxyeicosapentaenoic acids (HEPEs) may be a major mode of action by which EPA exerts its beneficial effects on glucose and lipid metabolism. Notably, cell culture and rodent studies show that HEPEs prevent fat accumulation in metabolic tissues through peroxisome proliferator activated receptor (PPAR)-mediated mechanisms. In addition, activation of the resolvin E1 pathway, either by administration of EPA in the diet or via intraperitoneal administration of resolvin E1, improves hyperglycemia, hyperinsulinemia, and liver steatosis through multiple mechanisms. These mechanisms include shifting immune cell phenotypes toward resolution of inflammation and preventing dysbiosis of the gut microbiome. Finally, we present the next steps for this line of research that will drive future precision randomized clinical trials with EPA and its downstream metabolites. These include dissecting the variables that drive heterogeneity in the response to EPA, such as the baseline microbiome profile and fatty acid status, circadian rhythm, genetic variation, sex, and age. In addition, there is a critical need to further investigate mechanisms of action for HEPEs and to establish the concentration of HEPEs in differing tissues, particularly in response to consumption of oily fish and EPA-enriched supplements.