Effects of the protein seum amyloid A on adipogenesis and production of inflammatory factors by adipocytes

• Grant number: 08/04678-3
• Support type: Regular Research Grants
• Duration: December 01, 2008 - November 30, 2010
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ana Campa
• Grantee: Ana Campa
• Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In the last few years, the concept that a low grade chronic inflammation accompanies the excessive expansion of the adipose tissue has emerged. The elements that associate the obesity with inflammation are: (i) a small increase in the amount of inflammatory factors in serum of obese individuals, (ii) the expression of inflammatory genes in adipocytes and (iii) the infiltration of macrophages into adipose tissue and its relationship with tissue growth. The inflammatory process in the growing adipose tissue has been hypothesized to be the primary event in the genesis of the metabolic and vascular alterations that accompanies obesity. Furthermore, it seems to be one of the conditions that associates obesity with diseases like diabetes type II and atherosclerosis.In the last two years we started a project in which the aim was to study the effect of the acute phase protein, serum amyloid A (SAA) on human adipocytes. The rationale for that study was the discovery that adipocytes were able to express SAA and the correlation between SAA and body mass index (BMI). Furthermore, obese individuals that loose weight had a reduction in the serum levels of SAA. We saw with very interest those studies because at that time our research group were studying the effect of SAA on cells of the immune system. In macrophages, neutrophils and mononuclear cells, SAA was able to induce responses characteristic of cellular activation and inflammation. SAA was able to induce the expression and release of a variety of cytokines, to increase the production of reactive oxygen (ROS) and nitrogen species (RNS).Initially our aim was to evaluate if those effects induced by SAA in leukocytes were also triggered in adipocytes. Preliminary results with human adipocytes isolated from subcutaneous adipose tissue isolated in esthetic surgery showed that adipocytes respond to SAA increasing the expression and release of the pro-inflammatory cytokines IL-6, IL-1², TNF-a and IL-8. There is strong evidence that the expression of the chemokine MIP-3± and the factors M-CSF, G-CSF e VEGF are also increased and that SAA modifies the uptake of glucose by adipocytes. These results were obtained during the pos-doc of Katia Aparecida de Almeida at my lab (FAPESP proc. No 05/58772-2). Analyzing these results in the view of the metabolic syndrome, we have a strong evidence to support to the idea that SAA is a key element in the association of inflammation and obesity. Thus, given the interest on this issue, Dr. Almeida spent 6 months at the lab of Dr.Stephen Farmer (Boston University). He is an expert in adipogenesis with useful knockdown and over expression molecular tools (FAPESP proc. No 07/52648-3). From the last July to December, Dr. Almeida studied the effect of SAA on the adipogenesis of murine preadipocytes 3T3-L1 cells and has prepared two cell models from 3T3-L1; a cell over expressing SAA and another one in which SAA was knockdown. Now, our aims are:1- To finalize the experiments of expression and release of cytokines and other factors induced by SAA on human adipocytes and to discuss these results in view of the metabolic syndrome;2- To finalize the experiments related to the modification of glucose uptake by SAA-stimulated adipocytes and to begin the study about lipid uptake;3- To conclude the experiments that shows that SAA inhibits adipogenesis in 3T3-L1 and the involvement of PPRA-³ e CEBP ± e ² pathways:4- To observe the effect of over expression or down expression of SAA on cell proliferation and differentiation;5- To evaluate the effect of SAA on proliferation and adipogenesis of human pre-adipocytes. (AU)