Fish Oil Improves Pathway-Oriented Profiling of Lipid Mediators for Maintaining Metabolic Homeostasis in Adipose Tissue of Prediabetic Rats

Abstract

Adipose tissue is now recognized as an active organ with an important homeostatic function in glucose and lipid metabolism and the development of insulin resistance. The present research investigates the role of lipid mediators and lipid profiling for controlling inflammation and the metabolic normal function of white adipose tissue from rats suffering from diet-induced prediabetes. Additionally, the contribution to the adipose lipidome induced by the consumption of marine ω-3 PUFAs as potential regulators of inflammation is addressed. For that, the effects on the inflammatory response triggered by high-fat high-sucrose (HFHS) diets were studied in male Sprague-Dawley rats. Using SPE-LC-MS/MS-based metabolo-lipidomics, a range of eicosanoids, docosanoids and specialized pro-resolving mediators (SPMs) were measured in white adipose tissue. The inflammatory response occurring in prediabetic adipose tissue was associated with the decomposition of ARA epoxides to ARA-dihydroxides, the reduction of oxo-derivatives and the formation of prostaglandins (PGs). In an attempt to control the inflammatory response initiated, LOX and non-enzymatic oxidation shifted toward the production of the less pro-inflammatory EPA and DHA metabolites rather than the high pro-inflammatory ARA hydroxides. Additionally, the change in LOX activity induced the production of intermediate hydroxides precursors of SPMs as protectins (PDs), resolvins (Rvs) and maresins (MaRs). This compensatory mechanism to achieve the restoration of tissue homeostasis was significantly strengthened through supplementation with fish oils. Increasing proportions of ω-3 PUFAs in adipose tissue significantly stimulated the formation of DHA-epoxides by cytochrome P450, the production of non-enzymatic EPA-metabolites and prompted the activity of 12LOX. Finally, protectin PDX was significantly reduced in the adipose tissue of prediabetic rats and highly enhanced through ω-3 PUFAs supplementation. Taken together, these actively coordinated modifications constitute key mechanisms to restore adipose tissue homeostasis with an important role of lipid mediators. This compensatory mechanism is reinforced through the supplementation of the diet with fish oils with high and balanced contents of EPA and DHA. The study highlights new insides on the targets for effective treatment of incipient diet-induced diabetes and the mechanism underlying the potential anti-inflammatory action of marine lipids.

Keywords: adipose tissue; inflammation; prediabetes; specialized resolvers; ω3 lipid mediators.

Figure 1

Comparison of lipid mediators formed in the perigonal adipose tissue of rats fed STD, STD+ω3, HFHS or HFHS+ω3 diets. (A). Balance of several EPA/ARA LOX-Hydroxides, particularly, 5HEPE/5HETE, 12HEPE/12HETE and 15HEPE/15HETE measured in adipose tissue from rats fed STD, STD+ω3, HFHS or HFHS+ω3 diets. (B). Balance of several Hydroxides/Hydroperoxides from EPA, particularly 12HEPE/12HpHEPE and 15HEPE/15HpHEPE, measured in in adipose tissue from rats fed STD, STD+ω3, HFHS or HFHS+ω3 diets. (C). Percentage of 11HETE in total ARA Hydroxides and percentage of 11HEPE in total EPA Hydroxides measured in adipose tissue from rats fed STD or HFHS diets. (D). Percentage of several DHA Hydroxides, particularly 4HDoHE, 11HDoHE, 14HDoHE and17HDoHE, in total LOX-Hydroxides measured in adipose tissue from rats fed STD or HFHS diets (n=9 per group). *Significant differences among groups (p < 0.05).