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Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4

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Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4 ORIGINAL ARTICLE Central Resistin Overexposure Induces Insulin Resistance Through Toll-like Receptor 4 Yacir Benomar,1,2 Arieh Gertler,3 Pamela De Lacy,4 Delphine Crépin,1,2 Hassina Ould Hamouda,1,2 Laure Riffault,1,2 and Mohammed Taouis1,2 Resistin promotes both inflammation and insulin resistance diabetes. Resistin is a cysteine-rich 12.5-kDa polypeptide associated with energy homeostasis impairment. However, the secreted by adipose tissue in rodents and by macrophages in resistin receptor and the molecular mechanisms mediating its humans (7,8), promoting inflammation and insulin resistance effects in the hypothalamus, crucial for energy homeostasis (9–12). Circulating resistin is increased in obese insulin- control, and key insulin-sensitive tissues are still unknown. In resistant rodents (6) and humans (7), and fasting decreases the current study, we report that chronic resistin infusion in the resistin mRNA expression (6,13). Peripheral administration lateral cerebral ventricle of normal rats markedly affects both or transgenic overexpression of resistin impairs insulin ac- hypothalamic and peripheral insulin responsiveness. Central tion in insulin-sensitive tissues (14–16). Conversely, deletion resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal–related kinase of the resistin gene or infusing of resistin antibodies or an- 1/2 associated with reduced IR expression and with upregulation tisense oligonucleotides restores insulin responsiveness of suppressor of cytokine signaling-3 and phosphotyrosine phos- (6,17–19). In humans, recent studies have linked resistin to phatase 1B, two negative regulators of insulin signaling. Addition- insulin resistance, atherosclerosis, and inflammation (12, ally, central resistin promotes the activation of the serine kinases 20,21). More recently, it has been shown that resistin is Jun NH2-terminal kinase and p38 mitogen-activated protein kinase, expressed in the hypothalamus (22) and activates specific enhances the serine phosphorylation of insulin receptor substrate- hypothalamic neurons (23). Central resistin also modulates 1, and increases the expression of the proinflammatory cytokine glucose homeostasis, lipid metabolism, and food intake and interleukin-6 in the hypothalamus and key peripheral insulin- impairs liver insulin sensitivity (24–27). sensitive tissues. Interestingly, we also report for the first time, to Resistin also regulates the synthesis and secretion of our knowledge, the direct binding of resistin to Toll-like receptor fl (TLR) 4 receptors in the hypothalamus, leading to the activation key proin ammatory cytokines such as tumor necrosis of the associated proinflammatory pathways. Taken together, our factor-a, interleukin (IL)-6, and IL-12 in macrophages via findings clearly identify TLR4 as the binding site for resistin in the a nuclear factor-kB–dependent pathway promoting insulin hypothalamus and bring new insight into the molecular mecha- resistance (4,6,28,29). Moreover, recent studies have pro- nisms involved in resistin-induced inflammation and insulin resis- vided evidence for the contribution of Toll-like receptor-4 tance in the whole animal. (TLR4) in the pathogenesis of obesity and insulin re- sistance. Saturated fatty acids activate both hypothalamic and peripheral TLR4 signaling, leading to proinflammatory cytokine production and endoplasmic reticulum stress he hypothalamus integrates hormonal and meta- (30–32). Conversely, TLR4 loss-of-function prevents satu- bolic signals to respond to energy body require- rated fatty acid-induced inflammation and insulin re- ments through the regulation of energy homeostasis sistance (30,31,33). Resistin and TLR4 have been linked to T(1,2). The disruption of this regulatory loop a proinflammatory process in a human epithelial cell line promotes the onset of obesity, currently considered a in which resistin competes with lipopolysaccharide (LPS) worldwide epidemic. Obesity is linked to common meta- for binding to TLR4 (34). Recently, an isoform of decorin bolic diseases including insulin resistance, which con- fi – was identi ed as a resistin receptor involved in white ad- stitutes a principal risk factor for type 2 diabetes (3 5). ipose tissue expansion (35). Another report has described Accumulating evidence indicates that changes in adipose- that mouse resistin modulates glucose uptake and pro- secreted factors in obesity, including release of inflamma- motes adipogenesis in 3T3-L1 cells through the receptor tory cytokines, dramatically affect insulin sensitivity (3–7). tyrosine kinase-like orphan receptor-1 (36). In addition, in Among these adipokines, resistin is described as a poten- rheumatoid arthritis disease, resistin has been shown to tial factor in obesity-mediated insulin resistance and type 2 use the IGF-1R signaling pathway (37). These data reveal a puzzling situation in which resistin could potentially in- teract with different receptors depending upon cellular From the 1Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France; the 2Centre National de la Recherche Scientifique, Center of Neuro- model. However, in vivo at the neuronal level, the resistin sciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France; the receptor and its signaling have not yet been identified. 3Faculty of Agricultural, Food and Environmental Quality Sciences, The Thus, we aimed to characterize hypothalamic resistin Institute of Biochemistry, Food Science, and Nutrition, The Hebrew Univer- sity of Jerusalem, Rehovot, Israel; and 4Shenandoah Biotechnology, Inc. receptor and its signaling pathways involved in the im- Warwick, Pennsylvania. pairment of insulin responsiveness. We show that resistin Corresponding author: Mohammed Taouis, [email protected]. signals through TLR4 in the hypothalamus lead to the ac- Received 28 February 2012 and accepted 6 July 2012. tivation of Jun NH -terminal kinase (JNK) and p38 mitogen- DOI: 10.2337/db12-0237 2 This article contains Supplementary Data online at http://diabetes activated protein kinase (MAPK) signaling pathways by the .diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0237/-/DC1. recruitment of the adaptor proteins myeloid differentiating Ó 2012 by the American Diabetes Association. Readers may use this article as factor 88 (MyD88) and Toll/interleukin-1 receptor domain- long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by containing adaptor protein (TIRAP), promoting overall in- -nc-nd/3.0/ for details. flammation. These findings reveal strong evidence for the diabetes.diabetesjournals.org DIABETES 1 Diabetes Publish Ahead of Print, published online September 6, 2012 HYPOTHALAMIC RESISTIN AND INSULIN RESISTANCE direct role of hypothalamic TLR4 signal transduction in transfection reagent according to the manufacturer’s guidelines. Down- resistin-induced whole-body inflammation and insulin re- regulation of the TLR4 protein synthesis following siRNA transfection was proved by Western blot analysis. sistance. 6 Cross-linking experiments. SH-SY5Y cells were plated at a density of 6 3 10 / 10-cm dish and serum-starved for 4 h before resistin treatment. Cells were then washed with ice-cold PBS (pH 8.0) to remove amine-containing culture RESEARCH DESIGN AND METHODS media and proteins from the cells and treated with resistin (100 ng/ml) for 10 Animals. Adult male Wistar rats weighing 250–300 g (Charles River Labora- min or 1 h at 4°C. The cross-linker BS3 (Thermo Fisher Scientific) was added tories, Paris, France) were used and had unrestricted access to water and directly to the incubation mixture to a final concentration of 2.5 mmol/L. After standard chow diet. Experimental procedures were performed according to an additional incubation for 1 h at 4°C, the cross-linking reaction was termi- the institutional guidelines approved by the governmental commission of an- nated by adding Tris-HCL solution (pH 7.4) to a final concentration of 20 imal research. mmol/L. Cells were solubilized in lysis buffer containing 20 mmol/L Tris-HCl Chronic intracerebroventricular infusion of resistin and intraperitoneal (pH 7.5), 137 mmol/L NaCl, 1 mmol/L MgCl2, 1 mmol/L CaCl2, 1% Nonidet P-40, insulin injection. Mini-osmotic pumps (model 2002; Alzet) were implanted 10% glycerol, proteases inhibitors, and phosphatases inhibitors. Protein lysates under ketamine (150 mg/kg; Vibrac, Lyon, France)/xylazine (5 mg/kg; Rompun; were then subjected to immunoprecipitation using anti-TLR4 antibody, and Bayer, Lyon, France) anesthesia. Brain infusion cannulae were stereotaxically immunoprecipitates were analyzed by Western blot using appropriate anti- placed into the lateral brain ventricle. The osmotic pumps were housed in bodies. a subcutaneous pocket on the dorsal surface of the animal. The rats were then Data analysis and statistics. Statistical analysis was performed using infused with either vehicle or resistin (1.2 mg/12 mL/day; pumping rate 0.5 mL/h) ANOVA (Statview Software program, version 5) to detect significant intergroup for 14 days. To test the impact of the central chronic resistin infusion on insulin differences. Data are presented as means 6 SEM, and a P value ,0.05 was sensitivity, overnight fasted rats were treated with insulin (1 U/kg of body considered statistically significant. weight) by intraperitoneal (IP) injection 30 min prior to euthanasia. Measurement of blood glucose and plasma hormones levels. Blood glu- cose levels were
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