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  • We also measured macrophage infiltration and


    We also measured macrophage infiltration and CLS presence in peri-gonadal AT from db/db mice and controls. CLS are morphological features within AT that are accurate indicators of adipocyte death and macrophage infiltration [56]. An earlier study showed that CLS macrophages account for >90% of the total adipose tissue macrophages in diabetic and insulin resistant mice and they display a pro-inflammatory phenotype [57]. Therefore, Mac-2+ CLS can be used as a surrogate for both adipocyte death and pro-inflammatory macrophage infiltration in adipose tissue. Recently, our group reported that 12LO protein in AT of diet-induced obese and insulin resistant mice is predominantly localized in CLS [58]. Moreover, both 12LO expression and the number of Mac-2 positive CLS are reduced in mice treated with the DPP4 inhibitor sitagliptin in parallel with improvement of insulin sensitivity and glucose tolerance [58]. In this paper we show an age-dependent dramatic increase in Mac-2+ CLS in perigonadal fat in db/db mice but not in heterozygous controls which is mirrored by an increase in 12-(S) HETE and 15(S)-HETE production in the same tissues. Therefore, a reduction in Mac-2+ CLS can be used as a marker to monitor anti-inflammatory effects of selective 12-LO inhibition in AT.
    Author’s contributions
    Introduction Polyunsaturated fatty acids (PUFAs) are essential fatty acids necessary in our diet on which various enzymes act to generate a variety of lipid metabolites that serve as signaling molecules required for normal cellular function [1]. The eicosanoids are metabolites generated from the oxidation of twenty-carbon omega-6 (ω-6) or omega-3 (ω-3) PUFAs that under certain conditions are pro-inflammatory [2,3]. One essential ω-6 PUFA is arachidonic GSK1838705A sale (AA). AA is normally esterified in the cell membrane phospholipids and released by phospholipase A2 in response to various peptides, such as growth factors and cytokines, induced by cellular stress [4]. AA then can be oxidized by three classes of enzymes to generate lipid products: the lipoxygenases (LOs) to generate leukotrienes, lipoxins, hepoxilins, hydroperoxyeicosatetraenoic acids (HpETEs), and hydroxyeicosatetraenoic acids (HETEs); the cyclooxygenases (COX-1 and COX-2) to generate prostaglandins and thromboxanes; and the cytochrome p-450 epoxygenases to generate epoxides [5]. In addition, LOs can act upon ω-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to generate lipid metabolites, such as the resolvins, maresins, and protectins, that directly act as anti-inflammatory metabolites or drive resolution of an acute inflammatory response [6]. Animal LO enzymes include 5-LO, 12-LO (epidermal-, platelet-, and leukocyte-type), 15-LO, and eLOX-3 (epidermis-type LO-3) (Table 1) named according to the carbon position at which they oxygenate their PUFA substrate [7]. The LOs are found in plants and animals, including humans, and are expressed from the LOX and ALOX genes, respectively (Table 1). However, comparison of the homologous isoforms across species is not always straightforward due to species-specific differences in affinity for different substrates and the products generated by the LO isoforms and thus care must be taken in interpreting data across species. Finally, the LOs are expressed in a variety of tissues including the vasculature, kidney, nervous system, liver, pancreatic islet, and adipose tissue [2,8–10]. For the purpose of this review, we will focus on the updated role of the 12- and 15-LOs in adipose tissue in the inflammatory obese condition. For a more comprehensive review covering the role of 12- and 15-LOs in tissues in both the normal and disease state, please refer to [2].
    12- and 15-lipoxygenases in the adipose tissue
    Conclusion Much is known about the role that the 12- and 15-LOs and their products play in both health and disease states. Their specific contribution in the process of inflammation is becoming clear, and as inflammation plays a major role in the development of two of the great epidemics of our time, obesity and diabetes, we must learn more about how these enzymes might be manipulated in order to develop therapeutic agents [103,104]. We must also study how our Western diet increases inflammation, and what role 12- and 15-LO pathways may play in that process [105]. Identification of downstream signaling components of the 12- and 15-LO enzymes as well as the recent discovery of the GPCR for 12(S)-HETE will aid in our understanding of these LOs. Furthermore, the development and description of selective inhibitors of human reticulocyte 15-LO-1 and human platelet-type 12-LO provide exciting opportunities for future research into the function (and dysfunction) of these enzymes [44–46].