Potential of circulating extracellular vesicles from exercised mice in the treatment of obesity.

Author(s)

Mariana de Mendonça

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2023-08-02

Examining board members

Alice Cristina Rodrigues; Luiz Osório Silveira Leiria; Edilamar Menezes de Oliveira; Ionara Rodrigues Siqueira

• Advisor: Alice Cristina Rodrigues

Abstract

Physical exercise is a non-pharmacological strategy widely used in the treatment of obesity. Through the secretion of molecules, loaded or not by extracellular vesicles (EVs), the skeletal muscle can communicate with other organs and vice versa and promote beneficial effects of physical exercise in obesity. Recently, it was shown that microRNAs (miRNAs) released in EVs both participate in the pathophysiology of obesity and may have a physiological action on the liver and adipose tissue after aerobic physical training. The objective of this work was to evaluate whether the beneficial effects promoted by physical exercise in obesity involve the release of miRNAs in EVs in the circulation, which are delivered to target tissues and thus participate in interorgan communication. We first evaluated possible changes in the profile of miRNAs contained in circulating EVs in response to aerobic training on a treadmill for 8 weeks in male C57BL6/J mice, control and diet obese. We demonstrated that in obese mice there is an increase in the expression of miRNAs (miR-122, miR-192 and miR-22) in serum EVs, which is reversed by chronic aerobic exercise. Associated with the reversion of miRs expression, the aerobic exercise protocol was able to reverse the non-alcoholic fatty liver disease (NAFLD), rescue brown adipose tissue thermogenesis and promote white adipose tissue adipogenesis. In control mice, chronic aerobic exercise increased miR-330 and miR133a miRNAs in circulating EVs. In order to evaluate the mechanism by which miRNAs in EVs act on obesity, we treated C57BL/6J mice with diet-induced obesity with EVs from control mice that performed aerobic exercise for 8 weeks. We demonstrate that treatment of obese mice with EVs from exercised mice serum simulates some of the effects seen in trained obese mice, such as improved insulin sensitivity, attenuation of NAFLD and decreased fat deposits. Furthermore, the treatment promoted remodeling of the adipose tissue with an increase in the proportion of smaller adipocytes and an increase in the expression of genes involved in the processes of adipogenesis, thermogenesis and markers of beige adipocytes, in addition to a significant increase in UCP1 content. In adipose tissue, such effects were associated with increased expression of miR-330 and miR-133a, delivered by circulating EVs from exercised animals used in the treatment. In conclusion, our data provide significant evidence that EVs mediate the effect of physical exercise on adipose tissue metabolism in obese mice and furthermore, these effects possibly involve the action of miRNAs contained in EVs that are delivered to adipose tissue. (AU)

• FAPESP's process: 17/19513-9 - Role of microRNAs in the regulation of adipokines and myocynes: understanding molecular mechanisms involved in the interaction between adipose tissue and skeletal muscle
• Grantee: Mariana de Mendonça
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)