The Potential Role of Exosomes in Child and Adolescent Obesity

Abstract

Child and adolescent obesity constitute one of the greatest contemporary public health menaces. The enduring disproportion between calorie intake and energy consumption, determined by a complex interaction of genetic, epigenetic, and environmental factors, finally leads to the development of overweight and obesity. Child and adolescent overweight/obesity promotes smoldering systemic inflammation ("para-inflammation") and increases the likelihood of later metabolic and cardiovascular complications, including metabolic syndrome and its components, which progressively deteriorate during adulthood. Exosomes are endosome-derived extracellular vesicles that are secreted by a variety of cells, are naturally taken-up by target cells, and may be involved in many physiological and pathological processes. Over the last decade, intensive research has been conducted regarding the special role of exosomes and the non-coding (nc) RNAs they contain (primarily micro (mi) RNAs, long (l) non-coding RNAs, messenger (m) RNAs and other molecules) in inter-cellular communications. Through their action as communication mediators, exosomes may contribute to the pathogenesis of obesity and associated disorders. There is increasing evidence that exosomal miRNAs and lncRNAs are involved in pivotal processes of adipocyte biology and that, possibly, play important roles in gene regulation linked to human obesity. This review aims to improve our understanding of the roles of exosomes and their cargo in the development of obesity and related metabolic and inflammatory disorders. We examined their potential roles in adipose tissue physiology and reviewed the scarce data regarding the altered patterns of circulating miRNAs and lncRNAs observed in obese children and adolescents, compared them to the equivalent, more abundant existing findings of adult studies, and speculated on their proposed mechanisms of action. Exosomal miRNAs and lncRNAs could be applied as cardiometabolic risk biomarkers, useful in the early diagnosis and prevention of obesity. Furthermore, the targeting of crucial circulating exosomal cargo to tissues involved in the pathogenesis and maintenance of obesity could provide a novel therapeutic approach to this devastating and management-resistant pandemic.

Keywords: adipose tissue; adolescent obesity; childhood obesity; epigenetics; exosomes; long non-coding RNAs; microRNAs.

Figure 1

Exosome biogenesis and secretion. Exosomes are generated by reverse invagination of the membrane and incorporation of RNA cargo and proteins during endosome maturation to multivesicular bodies (MVBs). The assembly of exosomes is regulated either by the recruitment of the endosomal sorting complex required for transport endosomal sorting complex required for transport (ESCRT) complex (ESCRT-dependent pathway), or by different proteins such as the tetraspanins, and the lipid ceramide (ESCRT-independent pathway). Subsequently, MVBs can follow several pathways: (1) fusion with the plasma membrane and exosome release; (2) fusion with lysosomes for content degradation; (3) participation in antigen presentation in the plasma membranes by major histocompatibility complex (MHC) class II molecules; and (4) recycling. Upon release, exosomes can interact with the plasma membranes of target cells and trigger downstream effects by (1) phagocytosis or endocytosis; (2) direct fusion of exosome membrane with recipient cell membrane; (3) direct interaction of exosome membrane protein with recipient surface cell receptor; (4) cleavage by proteases of exosome membrane proteins and binding of the resulting fragments to recipient cell receptors.