N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats

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da Silva, Karolline S. ; Pinto, Paula R. ; Fabre, Nelly T. ; Gomes, Diego J. ; Thieme, Karina ; Okuda, Ligia S. ; Iborra, Rodrigo T. ; Freitas, Vanessa G. ; Shimizu, Maria H. M. ; Teodoro, Walcy R. ; Marie, Suely K. N. ; Woods, Tom ; Brimble, Margaret A. ; Pickford, Russell ; Rye, Kerry-Anne ; Okamoto, Maristela ; Catanozi, Sergio ; Correa-Giannela, Maria L. ; Machado, Ubiratan F. ; Passarelli, Marisa

• Document type: Journal article
• Source: FRONTIERS IN PHYSIOLOGY; v. 8, SEP 22 2017.
• Web of Science Citations: 5

Abstract

Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and prevents insulin resistance. Therefore, it may be a useful tool in the prevention of AGE action on insulin resistance and long-term complications of DM. (AU)

• FAPESP's process: 16/15603-0 - Unraveling mechanisms of glycemic control and chronic complications of Diabetes mellitus: contributions to human health
• Grantee: Ubiratan Fabres Machado
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/12088-7 - Glycemic control and the removal of macrophage cholesterol by ABCA-1: role of modified albumin by advanced glycation
• Grantee: Rodrigo Tallada Iborra
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/15153-1 - Aerobic exercise training in wild type and CETP transgenic mice does not affect cellular cholesterol removal and expression of genes involved in lipid flux in macrophages and aortic arch
• Grantee: Paula Ramos Pinto
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 12/04831-1 - New players in glycemic control and chronic complications of Diabetes mellitus: preventive and therapeutic perspectives
• Grantee: Ubiratan Fabres Machado
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/18724-2 - Advanced glycated albumin and insulin resistance in rats: focus on periepididimal adipose tissue and N-acetylcysteine actions
• Grantee: Karolline Santana da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/17251-9 - The effects of chronic administration of albumin modified by advanced glycation (AGE) on renal tissue: characterization of the inflammatory, antioxidant and epigenetic profile
• Grantee: Karina Thieme
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/02854-7 - Anti-inflammatory role of apolipoprotein A-IV in diabetes mellitus and its impact on macrophage reverse cholesterol transport: influence of advanced glycation
• Grantee: Ligia Shimabukuro Okuda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral