Extracellular vesicles from adipocytes in cardiometabolic disease - Project Summary/Abstract Adipose tissue (AT) is a complex metabolic organ that functions to protect other tissues from lipotoxicity during overnutrition. It does this by storing lipids and modulating systemic metabolism though the release of adipokines. In obesity, AT becomes highly dysfunctional, leading to ectopic deposition of lipids in other tissues, systemic inflammation, insulin resistance, and oxidative stress. For this reason, dysfunctional AT is thought to contribute to most comorbidities of obesity including the development of type 2 diabetes and cardiovascular disease. From the discovery of leptin almost 30 years ago we have come to appreciate the robust role that adipokines have in inter-organ crosstalk to regulate metabolism in physiology and pathophysiology. Recently, us, and others, have demonstrated a new language that adipocytes use to communicate with other organs, extracellular vesicles (EVs). The language of EVs is powerful as these membrane-enclosed vesicles can carry any macromolecule including miRNAs, RNA, or enzymes, resulting in robust functional modulation of receiving cells at all levels of regulation, transcription, translation, and signaling. In the obese state, AT produces more EVs that, in vitro, propagate disease signals like inflammation and insulin resistance to other cells. The field of EVs in metabolic regulation is still in its infancy. In our published work we demonstrated that energetically stressed adipocytes release pieces of damaged mitochondria in EVs (mitoEVs) that enter circulation and have the capacity to respire and produce ATP. Adipocyte mitoEVs target the heart inducing mild oxidative stress, which is not pathogenic during acute exposure. Instead, a single injection of mitoEVs preconditions the heart to protect it from lethal levels of free radicals generated during ischemia/reperfusion. However, the preliminary data in this proposal suggests that long term treatment of mice with EVs from energetically stressed adipocytes has a negative impact on systemic metabolism, which may promote cardiac pathology during chronic obesity. Therefore, this proposal aims to understand the fundamental regulation of adipocyte-derived mitoEVs and if circulating mitoEVs become maladaptive over time, eventually contributing to cardiovascular disease. Ultimately, our goal is to determine if adipocyte EVs and mitoEVs are a viable target for therapeutic intervention. To do this we will focus on 2 aims: 1) Determine how the production and release of adipocyte mitoEVs is regulated under energetic stress and 2) Establish the consequences of chronically circulating adipocyte mitoEVs on obesity-related cardiometabolic disease in vivo.
