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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 40

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          Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.

          Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.
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            Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss.

            In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.
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              Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study.

              Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.
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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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