O papel da obesidade sobre o recrutamento de células-tronco mesenquimais da medula óssea

Abstract

Our group demonstrated that high fat diet-induced obesity induces bone marrow proinflammatory microenvironment, which programs the mesenchymal stem cells (BM-MSC) to pro-adipogenic phenotype (Silva et al., 2016). However, it is unclear whether obesity affects the BM-MSC recruitment to different tissues. In this study, we evaluated the role of high fat diet-induced obesity on the BM-MSC recruitment. Male C57Bl/ 6J mice at 21 days of age were fed with a high-fat diet (45% Kcal from fat) during 16 weeks (HFD group). The control group (CHOW group) were fed with a normal fat diet. The HFD animals presented an increase of body mass, higher food intake and a significative increase of body fat mass with a consequent decrease of the lean mass. In addition, we observed a higher fasting glucose and serum insulin levels, accompanied by glucose and insulin intolerance. The analysis of epididymal adipose tissue showed an increase in the fat mass and the presence of hypertrophic adipocytes. We also observed a higher leptin and IL-10 production in the supernatant of epididymal adipose tissue. No changes were observed in the surface markers expression or in the adipogenic differentiation, however, the BM-MSC from the HFD group had a greater proliferative potential when compared to CHOW group. Obesity induced an increase in the frequency of blood MSC, but no difference was observed in the content of these cells in the epididymal adipose tissue. We also observed an increase of MSC migration (in vitro) in the absence of the chemotactic agent. The challenge of SDF-1α (10nM chemotactic agent) not induced the MSC migration in the HFD group. No change was observed in the expression of the SDF-1α receptor, CXCR4, but we detected an increase in the activation of the PI3K / AKT pathway and a higher actin cytoskeletal polymerization in MSCs from obese animals. Finally, we not observed changes in the gene expression of SDF-1α in epididymal and subcutaneous adipose tissues. Our data suggest that high fat diet-induced obesity promotes insulin resistance, regardless of the presence of metainflammation. In addition, we showed that obesity promotes a migratory profile of BM-MSC without affecting its frequency in the epididymal adipose tissue. (Protocol CEUA: 024/2017)