12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by western diet

Abstract

Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.

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

“…These results indicate enhanced inflammation in adipocytes and adipose tissue of obese Zucker rats that is associated with increased 12-and 5-LO expression and activity. An earlier study from our laboratory demonstrated that in the high-fat-fed mouse model, global deletion of 12-LO significantly reduces macrophage infiltration and a proinflammatory response in visceral adipose tissue (43). Thus, we propose that 12-LO activation may be a link to adipose tissue inflammation in the insulin-resistant obese Zucker rats.…”

“…Furthermore, 12-LO has recently been linked to inflammation in high-fat diet-induced obesity in mice (43,54). 5-LO and 5-FLAP have also been implicated to play roles in obesity and insulin resistance (18,24,28), and a recent study demonstrated the role of 5-FLAP in adipose tissue inflammation in experimental obesity (24).…”

“…12-LO has been implicated in the development of atherosclerosis (40,53) and in the promotion of adipose tissue inflammation and insulin resistance in response to a high-fat diet (43,54). 12-LO expression and/or activity are upregulated by hyperglycemia (12,32,34,38,69) in pancreatic ␤-cells and mesangial cells, by free fatty acids such as palmitic acid in 3T3-L1 adipocytes (10), by inflammatory cytokines in pancreatic ␤-cells (12) and human islets (36), and in adipose tissue after mice are fed a Western diet (10,54).…”

12/15-Lipoxygenase Mediates High-fat Diet-induced Endothelial Tight Junction Disruption and Monocyte Transmigration

“…Because the majority of atherogenic risk factors are associated with increased 12/15-LO expression (5)(6)(7)(8), and disruption of 12/15-LO gene-protected ApoE Ϫ/Ϫ mice from developing high-fat diet-induced atherosclerosis (24), we studied the role of 12/15-LO in EC barrier dysfunction. A quiescent monolayer of HUVECs, when treated with 5-, 12-, and 15(S)-HETE, the AA cleavage products of 5-, 12-, and 15-LO, the paracellular permeability of the monolayer, as measured by passive diffusion of FITC-conjugated dextran, significantly increased (Fig.…”

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

“…In the NOD mouse, 12-lipoxygenase deletion confers a near complete protection against type 1 diabetes and also reduces immune cell activation [17,23]. Interestingly, two independent groups have shown that 12-lipoxygenase activation also participates in high-fat-induced insulin resistance and adipose tissue inflammation [24,25]. Deletion of 12-lipoxygenase significantly inhibits the development of insulin resistance in mice fed a high-fat diet.…”