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      Transgenic Increase in N-3/N-6 Fatty Acid Ratio Reduces Maternal Obesity-Associated Inflammation and Limits Adverse Developmental Programming in Mice

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          Abstract

          Maternal and pediatric obesity has risen dramatically over recent years, and is a known predictor of adverse long-term metabolic outcomes in offspring. However, which particular aspects of obese pregnancy promote such outcomes is less clear. While maternal obesity increases both maternal and placental inflammation, it is still unknown whether this is a dominant mechanism in fetal metabolic programming. In this study, we utilized the Fat-1 transgenic mouse to test whether increasing the maternal n-3/n-6 tissue fatty acid ratio could reduce the consequences of maternal obesity-associated inflammation and thereby mitigate downstream developmental programming. Eight-week-old WT or hemizygous Fat-1 C57BL/6J female mice were placed on a high-fat diet (HFD) or control diet (CD) for 8 weeks prior to mating with WT chow-fed males. Only WT offspring from Fat-1 mothers were analyzed. WT-HFD mothers demonstrated increased markers of infiltrating adipose tissue macrophages ( P<0.02), and a striking increase in 12 serum pro-inflammatory cytokines ( P<0.05), while Fat1-HFD mothers remained similar to WT-CD mothers, despite equal weight gain. E18.5 Fetuses from WT-HFD mothers had larger placentas ( P<0.02), as well as increased placenta and fetal liver TG deposition ( P<0.01 and P<0.02, respectively) and increased placental LPL TG-hydrolase activity ( P<0.02), which correlated with degree of maternal insulin resistance ( r = 0.59, P<0.02). The placentas and fetal livers from Fat1-HFD mothers were protected from this excess placental growth and fetal-placental lipid deposition. Importantly, maternal protection from excess inflammation corresponded with improved metabolic outcomes in adult WT offspring. While the offspring from WT-HFD mothers weaned onto CD demonstrated increased weight gain ( P<0.05), body and liver fat ( P<0.05 and P<0.001, respectively), and whole body insulin resistance ( P<0.05), these were prevented in WT offspring from Fat1-HFD mothers. Our results suggest that reducing excess maternal inflammation may be a promising target for preventing adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.

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          Most cited references 72

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          GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.

          Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation. Copyright 2010 Elsevier Inc. All rights reserved.
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            A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways.

            Obesity and type 2 diabetes are characterized by decreased insulin sensitivity, elevated concentrations of free fatty acids (FFAs), and increased macrophage infiltration in adipose tissue (AT). Here, we show that FFAs can cause activation of RAW264.7 cells primarily via the JNK signaling cascade and that TLR2 and TLR4 are upstream of JNK and help transduce FFA proinflammatory signals. We also demonstrate that F4/80(+)CD11b(+)CD11c(+) bone marrow-derived dendritic cells (BMDCs) have heightened proinflammatory activity compared with F4/80(+)CD11b(+)CD11c(-) bone marrow-derived macrophages and that the proinflammatory activity and JNK phosphorylation of BMDCs, but not bone marrow-derived macrophages, was further increased by FFA treatment. F4/80(+)CD11b(+)CD11c(+) cells were found in AT, and the proportion and number of these cells in AT is increased in ob/ob mice and by feeding wild type mice a high fat diet for 1 and 12 weeks. AT F4/80(+)CD11b(+)CD11c(+) cells express increased inflammatory markers compared with F4/80(+)CD11b(+)CD11c(-) cells, and FFA treatment increased inflammatory responses in these cells. In addition, we found that CD11c expression is increased in skeletal muscle of high fat diet-fed mice and that conditioned medium from FFA-treated wild type BMDCs, but not TLR2/4 DKO BMDCs, can induce insulin resistance in L6 myotubes. Together our results show that FFAs can activate CD11c(+) myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance.
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              Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.

              Metabolism and immunity are inextricably linked both to each other and to organism-wide function, allowing mammals to adapt to changes in their internal and external environments. In the modern context of obesogenic diets and lifestyles, however, these adaptive responses can have deleterious consequences. In this Review, we discuss the pleiotropic actions of inflammation and insulin resistance in metabolic homeostasis and disease. An appreciation of the adaptive context in which these responses arose is useful for understanding their pathogenic actions in disease.
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                Author and article information

                Affiliations
                [1 ]Division of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
                [2 ]Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
                Virgen Macarena University Hospital, School of Medicine, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MJRH JEF. Performed the experiments: MJRH MSS BAD RCJ. Analyzed the data: MJRH. Contributed reagents/materials/analysis tools: MJRH RCJ JEF. Wrote the paper: MJRH JEF.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                25 June 2013
                : 8
                : 6
                PONE-D-13-09183
                10.1371/journal.pone.0067791
                3692451
                23825686

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 13
                Funding
                The authors acknowledge support for this study from the National Institutes of Health DK-5R01DK062155, the Colorado Nutrition and Obesity Research (NORC) NIH P30 DK048520, the American Heart Association Predoctoral Fellowship AHA-11PRE5020014, and the Colorado Clinical Translational Science Institute T32 Grant TL1-RR-025778. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Embryology
                Systems Biology
                Medicine
                Endocrinology
                Diabetic Endocrinology
                Diabetes Mellitus Type 2
                Gestational Diabetes
                Insulin
                Reproductive Endocrinology
                Nutrition
                Obstetrics and Gynecology
                Pregnancy
                Pregnancy Complications
                Management of High-Risk Pregnancies
                Pediatrics
                Child Development
                Neonatology

                Uncategorized

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