12/15‐Lipoxygenase Products Induce Inflammation and Impair Insulin Signaling in 3T3‐L1 Adipocytes

Chakrabarti, Swarup K.; Cole, Banumathi K.; Wen, Yeong-Ray; Keller, Susanna R.; Nadler, Jerry L.

doi:10.1038/oby.2009.192

Cited by 123 publications

(141 citation statements)

References 37 publications

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“…7). A key role of the enzyme involved in PD1/PDX formation, 12/15 LOX, in adipose tissue inflammation and insulin resistance has been described [36,37]. The induction of prostaglandin 15d-PGJ 2 was an unexpected finding as 15d-PGJ 2 is derived from the metabolism of LC n-6 PUFA, and enzymatic formation of LC n-6 PUFA metabolites is, in general, inhibited upon LC n-3 PUFA supplementation.…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

et al. 2011

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Aims/hypothesis Calorie restriction is an essential component in the treatment of obesity and associated diseases. Longchain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. Methods Male mice (C57BL/6J) were habituated to a cornoil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF+F), ad libitum; (3) cHF with calorie restriction (CR; cHF+CR); and (4) cHF+F+CR. Mice fed a chow diet were also studied. Results We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ 12,15 -prostaglandin J 2 and protectin D1. Conclusions/interpretation White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

et al. 2011

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“…Although great attention has been focused on the COX-derived PG so far, emerging evidence suggests that LT as well as HETE LOX-catalyzed products may also exert profound biological effects on inflammation processes, being involved in the development and progression of specific human diseases, such as colorectal or pancreatic cancers (Comba and Pasqualini 2009;Di Mari et al 2007). In addition to their inflammatory role, 12-and 15-lipoxygenases have been reported as promoters of insulin resistance associated with obesity (Chakrabarti et al 2009) and osteoporosis (Almeida et al 2009). Interestingly, the same enzymes participating in the metabolism of omega-6 are involved in the metabolism of omega-3.…”

Section: Introductionmentioning

confidence: 99%

Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts

et al. 2013

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Metabolites derived from the polyunsaturated fatty acids (PUFA) may modulate the mesenchymal stromal cell (MSC) differentiation. Such cells can differentiate into different cellular types, including adipocytes and osteoblasts. Aging favors the bone marrow MSC differentiation toward the former, causing a loss of bone density associated with pathologies like osteoporosis. The omega-6 arachidonic acid (AA) favors MSC adipogenesis to a greater extent than omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this work, we study the joint action of both PUFA. Thus, not induced and induced to adipocyte or osteoblast MSC were treated with 20 lM of each PUFA (either AA, AA ? DHA or AA ? EPA). The expression of osteogenic and adipogenic molecular markers, the alox15b lipoxygenase gene expression and the 5-, 8-, 11-, 12-and 15-hydroxyeicosatetraenoic acids (HETE) derived from the AA metabolism in the culture media were determined. The results show that the adipogenesis induction of AA is not suppressed by the joint presence of EPA and DHA. In fact, both increased the adipogenic effect of AA on MSC differentiated into osteoblasts. The different HETE concentrations increased in cultures supplemented with AA, albeit such concentrations were lower in the cultures induced to differentiate, mainly at day 21 after the induction. Furthermore, the reduction in the HETE concentration was correlated with a higher expression of the alox15b gene. These results highlight the PUFA metabolism differences between uninduced and induced MSC to differentiate into adipocytes and osteoblasts, besides the relevant role of the lipoxygenase gene expression in adipogenesis induction.

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“…Isolation of white perigonadal adipocytes was performed as described previously (5,11). Briefly, rats were euthanized by CO 2 anaphyxiation.…”

Section: (S)-hpete] That Is Converted To the More Stable Product 12mentioning

confidence: 99%

Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats

Chakrabarti

Wen

Dobrian

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Central obesity is associated with low-grade inflammation that promotes type 2 diabetes and cardiovascular disease in obese individuals. The 12- and 5-lipoxygenase (12-LO and 5-LO) enzymes have been linked to inflammatory changes, leading to the development of atherosclerosis. 12-LO has also been linked recently to inflammation and insulin resistance in adipocytes. We analyzed the expression of LO and proinflammatory cytokines in adipose tissue and adipocytes in obese Zucker rats, a widely studied genetic model of obesity, insulin resistance, and the metabolic syndrome. mRNA expression of 12-LO, 5-LO, and 5-LO-activating protein (FLAP) was upregulated in adipocytes and adipose tissue from obese Zucker rats compared with those from lean rats. Concomitant with increased LO gene expression, the 12-LO product 12-HETE and the 5-LO products 5-HETE and leukotriene B4 (LTB4) were also increased in adipocytes. Furthermore, upregulation of key proinflammatory markers interleukin (IL)-6, TNFα, and monocyte chemoattractant protein-1 were observed in adipocytes isolated from obese Zucker rats. Immunohistochemistry indicated that the positive 12-LO staining in adipose tissue represents cells in addition to adipocytes. This was confirmed by Western blotting in stromal vascular fractions. These changes were in part reversed by the novel anti-inflammatory drug lisofylline (LSF). LSF also reduced p-STAT4 in visceral adipose tissue from obese Zucker rats and improved the metabolic profile, reducing fasting plasma glucose and increasing insulin sensitivity in obese Zucker rats. In 3T3-L1 adipocytes, LSF abrogated the inflammatory response induced by LO products. Thus, therapeutic agents reducing LO or STAT4 activation may provide novel tools to reduce obesity-induced inflammation.

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12/15‐Lipoxygenase Products Induce Inflammation and Impair Insulin Signaling in 3T3‐L1 Adipocytes

Cited by 123 publications

References 37 publications

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts

Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats

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