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.
Highlights
Adipose tissue is not considered anymore as an inert reservoir for energy but an immune organ with endocrine, paracrine and autocrine functions (1)
The rats were randomized into four groups (9 rats per group), and fed for 21 weeks one of the following diets: (a) a standard diet (2014 Teklad Global 14% Protein Diet from Envigo, IN, USA, STD control group), (b) a STD diet supplemented with fish oil eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) in a balanced 1:1 ratio (STD+w3) (c) a high-fat highsucrose (HFHS) diet (TD.08811 45% kcal fat diet from Envigo, IN, USA, HFHS control group), and (d) a HFHS diet supplemented with fish oil EPA/DHA in a balanced 1:1 ratio (HFHS+w3)
These results were in agreement with the worsen of insulin sensitivity and the increment of perigonadal white adipose tissue detected in these rats after 21 feeding weeks
Summary
Adipose tissue is not considered anymore as an inert reservoir for energy but an immune organ with endocrine, paracrine and autocrine functions (1). The storage capacity of adipocytes is exceeded, and further caloric overload leads to fat accumulation in ectopic tissues and visceral adipose depots, an event commonly defined as “lipotoxicity” (5). A high-energy state triggers uncontrolled inflammatory responses in white adipose tissue, leading to chronic low-grade inflammation and fostering the progression of insulin resistance. Within this context, a large amount of evidence indicates that the presence of persistent un-resolved adipose inflammation is addressed by a deregulated balance between the synthesis and release of pro-inflammatory lipid and peptide mediators by adipocytes and reduced levels of anti-inflammatory molecules (6, 7)
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