Adipocytes to heart inter-organ communication in the context of cardiac remodeling

Details

Supervisors

Balligand, Jean-Luc ; Michel, Lauriane

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents 50% of all heart failure (HF) patients experiencing similar HF clinical symptoms such as exertional dyspnea and exercise intolerance. Due to the heterogeneity in terms of phenotypes and comorbidities observed in HFpEF, the mechanisms underlying the pathophysiology of HFpEF are not fully understood and therefore have made the development of efficient therapies challenging. Obesity is a prominent comorbidity in HFpEF, which profoundly alters white adipose tissue (WAT) due to excessive lipid storage. Abdominal obesity, in particular, has been correlated with increased cardiovascular risks. The adipose tissue plays an important role in the endocrine communication with organs and participates in the regulation of metabolic homeostasis. Recent studies have demonstrated extracellular vesicles (EVs) as major mediators of intercellular communication with distinct sizes and cargos. However, the endocrine communication of WAT to the heart, particularly via EVs, remains to be elucidated. Notably, cardioprotective effects have been observed for thermogenic brown adipocytes from the brown adipose tissue (BAT) through EVs. Specific thermogenic adipocytes, so-called beige adipocytes, are also interspersed in WAT and their differentiation can be stimulated through the β3 adrenergic receptor (β3-AR). However, the influence of beige adipocytes on endocrine communication to the heart has never been dissected. Therefore, we hypothesize that adipose tissue dysfunction as observed in the context of obesity and its associated secreted EVs contributes to adverse cardiac remodeling, a major determinant of HFpEF progression and that stimulation of “beiging” in this context could be cardioprotective. Here, we used a mouse model fed with a high-fat diet for 5 months to mimic obesity-induced cardiac remodeling as well as a mouse model with repeated activation of the β3-AR using the agonist CL316,243 (CL) to model ‘beiging’ of WAT. Thereafter, secreted large (100-1000 nm) and small EVs (40-100 nm) were isolated from explanted adipose tissue and subjected to a complete characterization using several techniques. Isolated EVs from obese and control mice were then administered to primary neonatal cardiac myocytes (NRCM) in physiological conditions. In parallel, the cardioprotective capacity of EVs isolated from mice treated with CL was analysed on cardiac myocytes subjected to pro-hypertrophic treatment with phenylephrine. The impact of EVs on fibrotic response was also dissected when administered to primary cardiac fibroblasts in physiological conditions. The administration of EVs derived from obese mice increased the expression of some of the measured cardiac myocyte hypertrophic markers. In contrast, both small and large EVs derived from mice treated with CL attenuated the expression of all of these markers, suggesting that the beiging of adipose tissue might be a potent therapeutic strategy to prevent pro-hypertrophic action of obese adipose tissue via EVs.