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

Abstract

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.

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…The mechanisms controlling the balance between LTB 4 and LXA 4 production are, however, as yet unclear. Surprisingly, in aP2/Alox5ap transgenic mice, ALOX5AP overexpression led to higher levels of LXA 4 , whereas other reports have associated the increase in ALOX5/ALOX5AP in adipose tissue from rodent models of obesity with higher levels of LTB 4 (11,12,14,24). It has been reported that resolvin D1, another SPM, may increase LXA 4 and decrease LTB 4 production in macrophages (50).…”

“…LTB 4 , in addition to being a potent chemoattractant for leukocytes, enhances the release of proinflammatory adipokines, such as MCP-1 and interleukin (IL)-6, from obese adipose tissue (10,11). LTB 4 levels are elevated in adipose tissue during obesity (11)(12)(13), and LTB 4 has been described to play a role in the development of insulin resistance and to directly decrease insulin signaling in myocytes and hepatocytes in vitro (5,14,15). In addition, although the activation of the ALOX5/ALOX5AP complex is key to leukotriene synthesis, it can alternatively lead to the biosynthesis of other compounds, such as lipoxins (16).…”

“…Their expression is increased in adipose tissue of obese patients and animals with insulin resistance (11,12,23,24). Nevertheless, mice deficient for ALOX5 present an increase in body weight and body fat content and are more prone to fat accumulation when fed an HFD (13,25,26).…”

Bronchial asthma and obesity: search for therapeutic models

“…Кроме того, инфильтрация макрофага ми и секреция свободных жирных кислот возрастает параллельно с изменением уровня протеина, акти вирующего 5 ЛОГ. При инкубации жировой ткани с производными 5 ЛОГ отмечается рост секреции провоспалительных цитокинов, включая TNF [60,61]. В ряде работ приводятся свидетельства об улуч шении контроля над БА при применении лейкотри еновых антагонистов при ожирении, без уточнения специфического влияния ожирения [5].…”

12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

“…12/15-LO expression is upregulated in adipocytes from mice fed a high-fat diet and from insulin-resistant Zucker obese rats in vivo (6,7). 12/15-LO also induces inflammation, insulin resistance, and ␤-cell damage in vitro and in vivo, leading to whole body metabolic dysfunction (6 -8, 25, 33).…”