Exploring the role of adipose tissue-derived circulating miRNAs in the beneficial effects of exercise training

Abstract

The incidence of metabolic diseases reached global epidemics and prescription of exercise is among the safest and most efficacious alternatives to overcome this trend. Although effective, exercise training demands discipline and may not work for all individuals on the long term. Therefore, new adjuvant strategies or mimetic interventions may help patients to control their dysfunctional metabolism. Our group has found that increased miRNA biogenesis in adipose tissue is a common feature of both dietary restriction and exercise training, overcoming down-regulation that occurs with aging, obesity and lipodystrophy. Moreover, exclusive loss of miRNA biogenesis in adipocytes (i.e. the AdicerKO mice) leads to adipose tissue insulin resistance, and impaired oxidative metabolism and inflammation. Importantly, these mice also exhibit non-adipose phenotypes such as impaired muscle metabolism, whole body insulin resistance and increased risk of premature death. AdicerKO mice are also partially resistant to the beneficial effects of dietary restriction and exercise training. Recently we reported that the adipose tissue is the main source of circulating miRNAs in mice and possibly humans. Taken together, these observations lead us to hypothesize that adipose tissue derived circulating miRNAs (atdc-miRNAs) control part of the systemic effects of dietary restriction and exercise training and therefore participate in the pathophysiology of metabolic diseases. Here we will focus on the role of exercise in controlling atdc-miRNAs in mice and humans. We will test whether exercise training can reverse the metabolic complications of individuals with acquired lipodystrophy and if this is associated with changes in atdc-miRNAs. Moreover, we will define if and how atdc-miRNAs control the onset of immunosenescence in lipodystrophic humans and mice, given that impaired immune system is a hallmark of metabolic diseases. We thus aim to find atdc-miRNAs that mediate the crosstalk between the adipose tissue and the immune system to control the onset of metabolic diseases at a systemic level, thus contributing to the understanding of novel endocrine mechanisms. (AU)