Tocilizumab Increases Serum Adiponectin and Reduces Serum Fatty Acid Binding Protein 4 in Patients With Rheumatoid Arthritis

Background: Recently tocilizumab, a humanized anti-interleukin-6 receptor antibody (IL-6R Ab), was clinically demonstrated to ameliorate metabolic syndrome. However, it is unknown whether blocking the IL-6R with tocilizumab directly impacts the adiponectin and fatty acid-binding protein 4 (FABP4) levels. Methods: In this study, we measured the serum adiponectin and FABP4 levels in 18 patients with rheumatoid arthritis (RA) 3 months after treatment with tocilizumab. Results: Our study revealed that treatment with tocilizumab decreased serum FABP4 levels and increased serum adiponectin levels in patients with RA. We also assessed the production of adipocytokines stimulated by IL-6R Ab using adipocyte precursors obtained from human fat tissue. Tocilizumab did not increase local adiponectin levels; however, the suppression of adiponectin secretion by IL-6 was completely abolished. Tocilizumab also directly suppressed FABP4 in human adipocytes. Conclusion: This suggests that treatment with tocilizumab may be a novel approach to coordinately regulate adiponectin and FABP4 levels. J Endocrinol Metab. 2014;4(5-6):143-147 doi: http://dx.doi.org/10.14740/jem251w

[1]  F. Wolfe,et al.  Influence of nonclassical cardiovascular risk factors on the accuracy of predicting subclinical atherosclerosis in rheumatoid arthritis. , 2007, The Journal of rheumatology.

[2]  M. Suematsu,et al.  Capillary Endothelial Fatty Acid Binding Proteins 4 and 5 Play a Critical Role in Fatty Acid Uptake in Heart and Skeletal Muscle , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[3]  K. Maeda.  Role of adiponectin and adipocyte fatty acid binding protein in the metabolic syndrome. , 2007, Diabetes research and clinical practice.

[4]  O. Gavrilova,et al.  Thiazolidinediones improve insulin sensitivity in adipose tissue and reduce the hyperlipidaemia without affecting the hyperglycaemia in a transgenic model of type 2 diabetes , 2004, Diabetologia.

[5]  J. Berger,et al.  The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities , 2008, Molecular Pharmacology.

[6]  J. Suttles,et al.  The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. , 2005, The Journal of biological chemistry.

[7]  M. Genovese,et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. , 2008, Arthritis and rheumatism.

[8]  Mi Young Lee,et al.  Serum Adipocyte Fatty Acid–Binding Protein Levels Are Associated With Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Patients , 2009, Diabetes care.

[9]  L. Makowski,et al.  Fatty acid binding proteins--the evolutionary crossroads of inflammatory and metabolic responses. , 2004, The Journal of nutrition.

[10]  M. Laudes,et al.  Effects of Inhibition of Interleukin-6 Signalling on Insulin Sensitivity and Lipoprotein (A) Levels in Human Subjects with Rheumatoid Diseases , 2010, PloS one.

[11]  J. Suttles,et al.  The Fatty Acid-binding Protein, aP2, Coordinates Macrophage Cholesterol Trafficking and Inflammatory Activity , 2005, Journal of Biological Chemistry.

[12]  M. Kaplan.  Management of cardiovascular disease risk in chronic inflammatory disorders , 2009, Nature Reviews Rheumatology.

[13]  L. Nagy,et al.  Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases. , 2006, Endocrine, metabolic & immune disorders drug targets.

[14]  Ru-Ping Lee,et al.  Fasting serum level of fatty-acid-binding protein 4 positively correlates with metabolic syndrome in patients with coronary artery disease. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[15]  倉敷 有紀子,et al.  Measurement of adiponectin production from differentiated metabolic stem cells , 2010 .

[16]  S. Kusachi,et al.  Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients , 2011, Heart and Vessels.

[17]  K. Nakao,et al.  An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3‐L1 adipocytes , 2004, FEBS letters.

[18]  K. Shimamoto,et al.  Serum Fatty Acid-Binding Protein 4 Is a Predictor of Cardiovascular Events in End-Stage Renal Disease , 2011, PloS one.

[19]  R. Paschke,et al.  Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. , 2003, Biochemical and biophysical research communications.

[20]  U. Smith,et al.  Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not C/EBP alpha-evidence for differential regulation of the aP2 and adiponectin genes. , 2003, Biochemical and biophysical research communications.

[21]  Jennifer G. Robinson,et al.  The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis , 2012, The Lancet.

[22]  S. Kihara,et al.  Adiponectin and Metabolic Syndrome , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[23]  Jeffrey B. Boord,et al.  Combined Adipocyte-Macrophage Fatty Acid–Binding Protein Deficiency Improves Metabolism, Atherosclerosis, and Survival in Apolipoprotein E–Deficient Mice , 2004, Circulation.

[24]  M. Hochberg,et al.  Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity , 2010, Annals of the rheumatic diseases.

[25]  Y. Sadovsky,et al.  Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts. , 2007, American journal of obstetrics and gynecology.

[26]  G. Schett.  Rheumatoid arthritis and multiple sclerosis: Direful siblings, different strategies , 2011, FEBS letters.

[27]  Nader Rifai,et al.  Plasma adiponectin levels and risk of myocardial infarction in men. , 2004, JAMA.

[28]  J. Capeau,et al.  Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. , 2003, Biochemical and biophysical research communications.

[29]  Maia M. Jack,et al.  Adiponectin gene activation by thiazolidinediones requires PPARγ2, but not C/EBPα—evidence for differential regulation of the aP2 and adiponectin genes , 2003 .

[30]  U. Müller-Ladner,et al.  Adipocytokines as driving forces in rheumatoid arthritis and related inflammatory diseases? , 2011, Arthritis and rheumatism.

[31]  B. Cheung,et al.  Elevated Circulating Adipocyte‐Fatty Acid Binding Protein Levels Predict Incident Cardiovascular Events in a Community‐Based Cohort: A 12‐Year Prospective Study , 2013, Journal of the American Heart Association.

[32]  R. Straub,et al.  No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis , 2005, Annals of the rheumatic diseases.