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      • Record: found
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      Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance

      , , *

      Molecular and Cellular Endocrinology

      North Holland Publishing

      ABAF, anti-bacterial, anti-fungal, ANOVA, analysis of variance, AS160, Akt substrate of 160 kDa, BSA, bovine serum albumin, CM, conditioned medium, CXCL2, Chemokine (C-X-C motif) ligand 2, DMEM, Dulbecco’s modified Eagle's medium, DMSO, dimethylsulphoxide, ERK, extracellular signal-related kinase, FA, fatty acid, FBS, foetal bovine serum, GLUT, glucose transporter, GSK, glycogen synthase kinase, IKK, inhibitor κ kinase, IκBα, inhibitor κBα, IL, interleukin, iNOS, inducible nitric oxide synthase, IR, insulin resistance, IRS1, insulin receptor substrate-1, JNK, C-jun n-terminal kinase, LPS, lipopolysaccharide, mac, macrophage, MAPK, mitogen-activated protein kinase, MCP1, monocyte chemoattractant protein, NFκB, nuclear factor-κB, PI3K, phosphoinositol 3-kinase, palm, palmitate, PBS, phosphate-buffered saline, PKC, protein kinase C, PMA, phorbol myristate acetate, RIPA, radioimmunoprecipitation, SDS-PAGE, sodium dodecyl sulphate, polyacrylamide gel electrophoresis, SFA, saturated fatty acid, siRNA, small interfering RNA, T2D, type 2 diabetes, TLR, Toll-like Receptor, TNFα, tumour necrosis factor-α, UFA, unsaturated fatty acid, Fatty acid, Tumour necrosis factor-α, p38 Mitogen-activated protein kinase, Insulin resistance, Skeletal muscle, Macrophage

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          Highlights

          • Palmitate-treated macrophage-conditioned medium causes myotube insulin resistance.
          • This involves activation of myotube p38 mitogen activated protein kinase.
          • Conditioned medium effects are mediated by tumour necrosis factor-α.
          • These effects are prevented by addition of palmitoleate.
          • Palmitoleate treatment of macrophages is insulin sensitising for myotubes.

          Abstract

          Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.

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          Most cited references 66

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          Obesity is associated with macrophage accumulation in adipose tissue.

          Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.
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            Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

            Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
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              • Record: found
              • Abstract: found
              • Article: not found

              TLR4 links innate immunity and fatty acid-induced insulin resistance.

              TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
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                Author and article information

                Contributors
                Journal
                Mol Cell Endocrinol
                Mol. Cell. Endocrinol
                Molecular and Cellular Endocrinology
                North Holland Publishing
                0303-7207
                1872-8057
                05 August 2014
                05 August 2014
                : 393
                : 1-2
                : 129-142
                Affiliations
                Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK
                Author notes
                [* ]Corresponding author. Tel.: +44 20 7468 5269; fax: +44 20 7468 5204. mcleasby@ 123456rvc.ac.uk
                Article
                S0303-7207(14)00193-2
                10.1016/j.mce.2014.06.010
                4148479
                24973767
                © 2014 The Authors
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