Omega‐3‐polyunsaturated fatty acids (w‐3‐PUFAs) have well‐documented protective effects that are attributed not only to eicosanoid inhibition but also to the formation of novel biologically active lipid mediators (i.e ., resolvins and protectins). In this study, we examined their effects on ob/ob mice, an obesity model of insulin resistance and fatty liver disease. Dietary intake ofw‐3‐PUFAs had insulin‐sensitizing actions in adipose tissue and liver and improved insulin tolerance in obese mice. Genes involved in insulin sensitivity (PPAR/γ), glucose transport (GLUT‐2/GLUT–4), and insulin receptor signaling (IRS‐1/IRS–2) were up‐regulated byw‐3‐PUFAs. Moreover,w‐3‐PUFAs increased adiponectin, an anti‐inflammatory and insulin‐sensitizing adipokine, and induced AMPK phosphorylation, a fuel‐sensing enzyme and a gatekeeper of the energy balance. Concomitantly, hepatic steatosis was alleviated byw‐3‐PUFAs. A lipidomic analysis with liquid chromatography/mass spectrome‐try/mass spectrometry revealed that w‐3‐PUFAs inhibited the formation of w‐6‐PUFA‐derived eicosanoids, while triggering the formation of w‐3‐PUFA‐derived resolvins and protectins. Moreover, representative members of these lipid mediators, namely resolvin E1 and protectin D1, mimicked the insulin‐sensitizing and antisteatotic effects of w‐3‐PUFAs and induced adiponectin expression to a similar extent that of rosigli‐tazone, a member of the thiazolidinedione family of antidiabetic drugs. Taken together, these findings uncover beneficial actions of w‐3‐PUFAs and their bioactive lipid autacoids in preventing obesity‐induced insulin resistance and hepatic steatosis.—Gonzalez‐Periz, A.,Horrillo, R., Ferre, N., Gronert, K., Dong, B., Moran‐Salvador, E.,Titos, E., Martinez‐Clemente, M.,Lopez‐Parra, M.,Arroyo, V., Claria, J. Obesity‐induced insulin resistance and hepatic steatosis are alleviated byw‐3 fatty acids: a role for resolvins and protectins. FASEB J. 23, 1946–1957 (2009)

The presence of the so-called low-grade inflammatory state is recognized as a critical event in adipose tissue dysfunction, leading to altered secretion of adipokines and free fatty acids (FFAs), insulin resistance, and development of hepatic complications associated with obesity. This study was designed to investigate the potential contribution of the proinflammatory 5-lipoxygenase (5-LO) pathway to adipose tissue inflammation and lipid dysfunction in experimental obesity. Constitutive expression of key components of the 5-LO pathway, as well as leukotriene (LT) receptors, was detected in adipose tissue as well as in adipocyte and stromal vascular fractions. Adipose tissue from obese mice, compared with that from lean mice, exhibited increased 5-LO activating protein (FLAP) expression and LTB₄ levels. Incubation of adipose tissue with 5-LO products resulted in NF-κB activation and augmented secretion of proinflammatory adipokines such as MCP-1, IL-6, and TNF-α. In addition, LTB₄, but not LTD₄, reduced FFA uptake in primary adipocytes, whereas 5-LO inhibition suppressed isoproterenol-induced adipose tissue lipolysis. In mice with dietary obesity, elevated FLAP expression in adipose tissue was paralleled with macrophage infiltration, increased circulating FFA levels, and hepatic steatosis, phenomena that were reversed by FLAP inhibition with Bay-X-1005. Interestingly, FLAP inhibition induced AMP-activated protein kinase phosphorylation in parallel with decreases in hormone-sensitive lipase activity and the expression and secretion of TNF-α and IL-6. Similar effects were observed in differentiated 3T3-L1 adipocytes incubated with either Bay-X-1005 or the selective LTB₄ receptor antagonist U-75302. Taken together, these findings indicate that the 5-LO pathway signals the adipose tissue low-grade inflammatory state and steatogenic potential in experimental obesity.

Dietary habits established in infancy may persist into adulthood and determine long-term health. The aims of this work were to describe dietary patterns, predictors of adherence to them, and their tracking from ages 1 to 8 y in European children. Three-day food diaries were prospectively collected at ages 1, 2, 3, 4, 5, 6 and 8 y. Foods were allocated to 1 of 29 food groups, which were included in exploratory factor analyses at each children's age. The tracking of patterns through childhood was assessed by an estimated general equation model. At age 1 y (n = 633), 2 patterns were identified. One was labeled “core foods” (CORE), since it was positively loaded for vegetables, fish, olive oil, and white and red meat, and negatively loaded for ready-to-eat infant products, sugar, and confectioneries. The other was positively loaded for saturated spreads, sugar, fruit juices, and confectioneries, and negatively loaded for olive oil, fish, and cow milk; this was labeled as the “poor-quality fats and added sugars” (F&S) pattern. From ages 2 to 8 y, 3 patterns were repeatedly identified: CORE, F&S, and a “high protein sources” (PROT) pattern that was positively loaded for milk, flavored milks, fish, eggs, white and processed meat, chips, and olive oil, and negatively loaded for fresh fruits at almost all time points. Of those children in the highest quartiles of the CORE, F&S, and PROT patterns at 2 y, 45%, 72%, and 36%, respectively, remained in the highest quartile at 8 y [OR = 2.01 (1.08, 3.8), OR = 3.6 (1.5, 8.4) and OR = 0.80 (0.4,1.6), respectively; P = 0.510]. Dietary patterns are established between 1 and 2 y of age and track into mid-childhood. A dietary pattern characterized by added sugars, unhealthy fats, and poor consumption of fish and olive oil was the most stable throughout childhood. Further analyses will reveal whether those dietary patterns are associated with metabolic disease risk.

The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia-prone apolipoprotein E–deficient (ApoE−/−) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to be up-regulated in these mice and given that 5-LO deficiency confers cardiovascular protection to ApoE−/− mice, we determined the extent to which the absence of 5-LO would alter liver injury in these mice. Compared with ApoE−/− mice, which showed expected hepatic steatosis and inflammation, ApoE/5-LO double-deficient (ApoE−/−/5-LO−/−) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-κB (NF-κB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue because peroxisome proliferator-activated receptor γ, insulin receptor substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the other hand, hepatocytes isolated from ApoE−/−/5-LO−/− mice were more resistant to TNF-α–induced apoptosis. The 5-LO products leukotriene (LT) B4, LTD4, and 5-HETE consistently triggered TNF-α–induced apoptosis and compromised hepatocyte survival by suppressing NF-κB activity in the presence of actinomycin D. Moreover, ApoE−/−/5-LO−/− mice were protected against sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE−/− mice. Finally, pharmacological inhibition of 5-LO significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models of fatty liver disease. Conclusion: These combined data indicate that hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory injury, suggesting that 5-LO is involved in mounting hepatic inflammation in metabolic disease. (Hepatology 2010.)