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Blocking CD40-TRAF6 Interactions by Small-Molecule Inhibitor 6860766 Ameliorates the Complications of Diet-Induced Obesity in Mice

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Blocking CD40-TRAF6 Interactions by Small-Molecule Inhibitor 6860766 Ameliorates the Complications of Diet-Induced Obesity in Mice International Journal of Obesity (2015) 39, 782–790 © 2015 Macmillan Publishers Limited All rights reserved 0307-0565/15 www.nature.com/ijo ORIGINAL ARTICLE Blocking CD40-TRAF6 interactions by small-molecule inhibitor 6860766 ameliorates the complications of diet-induced obesity in mice SM van den Berg1,7, TTP Seijkens1,7, PJH Kusters1, B Zarzycka2, L Beckers1, M den Toom1, MJJ Gijbels1,3,4, A Chatzigeorgiou5, C Weber2,6, MPJ de Winther1, T Chavakis5, GAF Nicolaes2 and E Lutgens1,6 BACKGROUND: Immune processes contribute to the development of obesity and its complications, such as insulin resistance, type 2 diabetes mellitus and cardiovascular disease. Approaches that target the inflammatory response are promising therapeutic strategies for obesity. In this context, we recently demonstrated that the interaction between the costimulatory protein CD40 and its downstream adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes adipose tissue inflammation, insulin resistance and hepatic steatosis in mice in the course of diet-induced obesity (DIO). METHODS: Here we evaluated the effects of a small-molecule inhibitor (SMI) of the CD40-TRAF6 interaction, SMI 6860766, on the development of obesity and its complications in mice that were subjected to DIO. RESULTS: Treatment with SMI 6860766 did not result in differences in weight gain, but improved glucose tolerance. Moreover, SMI 6860766 treatment reduced the amount of CD45+ leucocytes in the epididymal adipose tissue by 69%. Especially, the number of adipose tissue CD4+ and CD8+ T cells, as well as macrophages, was significantly decreased. CONCLUSIONS: Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile. International Journal of Obesity (2015) 39, 782–790; doi:10.1038/ijo.2014.198 INTRODUCTION cardiovascular disease.5–10 Strategies that modulate the inflam- Obesity and its associated conditions, including insulin resistance, matory response are therefore promising therapeutic modalities type 2 diabetes mellitus and cardiovascular diseases, affect more for obesity and its complications. than 1000 million people worldwide, a number that is increasing The costimulatory dyad CD40 and its ligand CD40L (CD154) and is expected to do so for the next decades.1,2 Chronic caloric have a well-known role in immune cell activation and fl 11 excess may shorten healthy lifespan of humans by 5 − 20 years, in ammation. After binding of CD40L, CD40 recruits adaptor which results in a tremendous socioeconomic burden.1 Hence, the proteins, the tumor necrosis factor receptor-associated factors (TRAFs).11 The intracellular domain of CD40 contains two binding development of novel therapeutic strategies for obesity and its sites for these proteins: a proximal site that binds TRAF2/3/5 and a related disorders is a public health priority. distal site that binds TRAF6.11 After binding of the TRAF proteins Over the past decades, chronic inflammation has been to CD40, signal transduction is initiated, which eventually results identified as the pathological substrate of obesity and its 11 1,3,4 in the expression of inflammatory mediators. Mice with a complications. Elevated plasma levels of cytokines, such as genetic deficiency in the CD40-TRAF6 interaction, but not in the tumor necrosis factor and interleukin-6 (IL-6), characterize obese CD40-TRAF2/3/5 interaction, are protected against the develop- subjects and show a positive correlation with the extent of 5–9 ment of neointima formation and atherosclerosis, both exponents metabolic dysfunction. Obese adipose tissue (AT) exhibits of an ongoing inflammatory condition of the arterial wall.12,13 hallmarks of an ongoing inflammatory response, such as immune Accumulating evidence indicates that the CD40-CD40L dyad cell infiltration and activation, as well as the presence of has an important role in obesity.6,14–17 For example, plasma levels proinflammatory cytokines and adipokines, including tumor of soluble CD40L correlate with the body mass index in obese – necrosis factor, IL-6 and leptin.5 9 Moreover, chronic inflammation subjects and decrease after bariatric surgery.14 CD40-CD40L- has a pivotal role in the development of obesity-associated mediated interactions between adipocytes and AT immune cells, diseases, such as hepatic steatosis, type 2 diabetes mellitus and including T cells and macrophages, promote the expression of 1Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands; 3Department of Pathology, Maastricht University, Maastricht, The Netherlands; 4Department of Molecular Genetics, Maastricht University, Maastricht,The Netherlands; 5Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany and 6Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian’s University, Munich, Germany. Correspondence: Professor Dr E Lutgens, Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands. E-mail: [email protected] 7These authors contributed equally to this work. Received 4 September 2014; revised 10 October 2014; accepted 27 October 2014; accepted article preview online 13 November 2014; advance online publication, 9 December 2014 SMI-mediated CD40-TRAF6 inhibition in obesity SM van den Berg et al 783 proinflammatory cytokines and chemokines, which increase the mice were treated daily with SMI 6860766 (10 μmol kg − 1)(n = 12) or recruitment of other inflammatory cells to the AT.15,16 Ligation of vehicle (0.05% Tween-80, 5% dimethyl sulphoxide in phosphate-buffered CD40 on adipocytes promotes insulin resistance by decreasing saline)19 (n = 12) for 6 weeks. Mice had ad libitum access to food and water insulin receptor substrate-1 and glucose transporter type 4 and were maintained under a 12 h light–dark cycle. Food intake and body expression.15,16 Genetic deficiency or antibody-mediated inhibition weight were measured weekly. After the experimental procedure, mice of CD40L reduced the inflammatory and metabolic complications of were fasted overnight and subsequently killed. Blood was collected and fl diet-induced obesity (DIO).15,16 In contrast, deficiency of CD40 organs were dissected and processed for ow cytometric and histological aggravates the complications of DIO.18–20 To understand these analysis. All experimental procedures were approved by the Animal Experimentation Ethics Committee of the University of Amsterdam. opposing effects of CD40L and CD40, we previously investigated the role of different downstream adaptor proteins of the CD40-CD40L pathway. We found that deficiency of CD40-TRAF2/3/5 interactions Haematology and biochemical measurements increased the metabolic and inflammatory complications of DIO, Blood was obtained by cardiac puncture with EDTA-filled syringes. whereas deficiency of CD40-TRAF6 interactions rather improved AT Haematological analysis was performed on a ScilVet abc plus+ (ScilVet, inflammation and insulin resistance in DIO mice. Based on these Oostelbeers, The Netherlands). data, we developed a small-molecule inhibitor (SMI) against CD40- TRAF6 interactions, and we could show that treatment with SMI Insulin assay and calculation of HOMA-IR 6877002 improved insulin resistance, hepatic steatosis and M1 Fasting insulin was measured in plasma by enzyme-linked immunoabsor- macrophage accumulation into the epididymal AT (EpAT), when bent assay (Mercodia, Uppsala, Sweden) following the manufacturer's treatment was initiated 6 weeks after the beginning of the diet.19 protocol. Glucose levels were measured from whole blood upon killing Thus, inhibition of the CD40-TRAF6 interaction is a promising using a glucometer (Bayercontour, Basel, Switzerland). The homeostasis therapeutic strategy for obesity. model assessment of insulin resistance (HOMA-IR) was calculated using the − 1 Here we performed a more thorough analysis of the effects of following formula: HOMA-IR = fasting glucose (mmol l ) × fasting insulin − 1 SMI-mediated CD40-TRAF6 inhibition in DIO. We investigated the (m U l )/22.5. effects of SMI 6860766, an analogue of 6877002 with a lower IC50 (half-maximal inhibitory concentration),19 in DIO. In addition, we Glucose tolerance test here administered the CD40-TRAF6 inhibitor after 12 weeks of One week before and 3 and 6 weeks after the initiation of SMI 6860766 or high-fat diet (HFD), when obesity was much more progressed, and vehicle treatment, a glucose tolerance test was performed. Twelve-hour continued diet and treatment until week 18. Our data suggest that fasted mice were injected intraperitoneally with glucose (1 mg g − 1; Sigma- SMI-mediated CD40-TRAF6 inhibition is a promising novel Aldrich, Zwijndrecht, The Netherlands). Glucose levels were measured from therapeutic approach in DIO-related metabolic dysregulation. whole blood using a glucometer (Bayercontour, Basel, Switzerland) at times indicated in the figures. MATERIALS AND METHODS Real-time PCR TRAF6 C-domain expression, purification
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