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Adipose-Derived Exosomes As Possible Players in the Development of Insulin Resistance

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Adipose-Derived Exosomes As Possible Players in the Development of Insulin Resistance International Journal of Molecular Sciences Review Adipose-Derived Exosomes as Possible Players in the Development of Insulin Resistance Arkadiusz Zbikowski˙ 1 , Agnieszka Błachnio-Zabielska 2 , Mauro Galli 1 and Piotr Zabielski 1,* 1 Department of Medical Biology, Medical University of Bialystok, 15-089 Białystok, Poland; [email protected] (A.Z.);˙ [email protected] (M.G.) 2 Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, 15-089 Białystok, Poland; [email protected] * Correspondence: [email protected] Abstract: Adipose tissue (AT) is an endocrine organ involved in the management of energy metabolism via secretion of adipokines, hormones, and recently described secretory microvesicles, i.e., exosomes. Exosomes are rich in possible biologically active factors such as proteins, lipids, and RNA. The secretory function of adipose tissue is affected by pathological processes. One of the most important of these is obesity, which triggers adipose tissue inflammation and adversely affects the release of beneficial adipokines. Both processes may lead to further AT dysfunction, contributing to changes in whole-body metabolism and, subsequently, to insulin resistance. According to recent data, changes within the production, release, and content of exosomes produced by AT may be essential to un- derstand the role of adipose tissue in the development of metabolic disorders. In this review, we summarize actual knowledge about the possible role of AT-derived exosomes in the development of insulin resistance, highlighting methodological challenges and potential gains resulting from exosome studies. Citation: Zbikowski,˙ A.; Błachnio-Zabielska, A.; Galli, M.; Keywords: adipose tissue; metabolic disorders; insulin resistance; type 2 diabetes; adipokines; exosomes Zabielski, P. Adipose-Derived Exosomes as Possible Players in the Development of Insulin Resistance. Int. J. Mol. Sci. 2021, 22, 7427. 1. Introduction https://doi.org/10.3390/ijms22147427 Adipose tissue (AT) is a multifunctional organ distributed across the human body in numerous locations. There are two main types of AT: brown adipose tissue (BAT) Academic Editor: Amedeo Lonardo and white adipose tissue (WAT). Based on its localization, WAT can be divided into two major depots: subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) [1]. Received: 29 April 2021 Both tissue depots are endocrine organs, and their functional and different metabolic Accepted: 9 July 2021 Published: 11 July 2021 properties create a balance that contributes to the maintenance of energy homeostasis in the body [2]. This balance may be interrupted by obesity, a non-physiological WAT Publisher’s Note: MDPI stays neutral accumulation. The prevalence of obesity is continually on the rise in both developed and with regard to jurisdictional claims in developing countries. The World Health Organization reported that, in 2016, more than published maps and institutional affil- 650 million adults were obese. Responsibility for this situation is primarily attributed to iations. decreased physical activity and an increased intake of high-energy foods that are rich in saturated fats and sugars. Obesity may lead to numerous health comorbidities, such as cardiovascular disease, musculoskeletal disorders, cancer (including endometrial, prostate, breast, ovarian, liver, gallbladder, kidney, and colon), and, finally, insulin resistance (IR) and type 2 diabetes (T2D). Insulin resistance is a state in which insulin-responsive tissue Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (skeletal muscle, liver, adipose depots) fails to properly respond to physiological insulin This article is an open access article levels, and it is strongly associated with obesity. Mechanisms linking IR with obesity are distributed under the terms and complex; however, low-grade chronic inflammation of adipose tissue and disturbances conditions of the Creative Commons in the production and secretion of numerous adipokines are common denominators [3]. Attribution (CC BY) license (https:// Endocrine functions of adipose tissue have been under continuous investigation since creativecommons.org/licenses/by/ the 1980s, resulting in hundreds of potential bioactive secretory proteins and peptides [4]. 4.0/). Among these, leptin, adiponectin, resistin, and retinol-binding protein 4 (RBP4) have Int. J. Mol. Sci. 2021, 22, 7427. https://doi.org/10.3390/ijms22147427 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 vestigation since the 1980s, resulting in hundreds of potential bioactive secretory proteins and peptides [4]. Among these, leptin, adiponectin, resistin, and retinol-binding protein 4 Int. J. Mol. Sci. 2021, 22, 7427 (RBP4) have been studied extensively, which has led to the formulation of the 2definition of 15 of adipokines. Currently, adipokines are recognized as central regulators of insulin sen- sitivity, metabolism, and energy homeostasis. However, the full profile of adipose se- cretome—inbeen studied the extensively, form of metabolites, which has led proteins to the formulation, and secretory of the vesicles—is definition of adipokines.still under con- tinuousCurrently, research adipokines [5,6]. are recognized as central regulators of insulin sensitivity, metabolism, andA energyrelatively homeostasis. new area However, of studies the has full since profile emerged, of adipose one secretome—in that is dedicated the form to ofthe ex- plorationmetabolites, of WAT proteins, secretome, and secretory and more vesicles—is specifically still under to WAT-derived continuous research secretory [5,6]. extracel- lular vesiclesA relatively (EVs). new EVs area are ofsmall studies membrane- has sincederived emerged, vesicles one that secreted is dedicated into extracellular to the space.exploration Based ofon WAT the secretome,differences and in more secretion specifically mechanisms to WAT-derived and the secretory size of extracellular the particular EVs,vesicles secretory (EVs). vesicles EVs are smallare divided membrane-derived into three vesiclesmain types: secreted (1) into apoptotic extracellular bodies, space. (2) mi- Based on the differences in secretion mechanisms and the size of the particular EVs, crovesicles, and (3) exosomes. Apoptotic bodies, or blebs, with a diameter roughly above secretory vesicles are divided into three main types: (1) apoptotic bodies, (2) microvesicles, 1µm,and are (3) exosomes.released during Apoptotic the bodies, apoptosis or blebs, of a with cell a [7]. diameter Microvesicles roughly above are medium-sized 1 µm, are structuresreleased (100nm–1µm) during the apoptosis that originate of a cell [from7]. Microvesicles the plasma aremembrane medium-sized through structures the process of (100blebbing. nm–1 µThem) thatmicrovesicle originate from membrane the plasma cont membraneains surface through antigens, the process receptors, of blebbing. and chan- nelsThe of microvesicle the parent membranecell. The biogenesis contains surface and antigens,secretion receptors, of microvesicles and channels is an of theATP- parent and cal- cium-dependentcell. The biogenesis process. and secretionExosomes, of microvesiclesin turn, display is an the ATP- smallest and calcium-dependent diameter (30–100nm) and,process. contrary Exosomes, to the above in turn, EVs, display they the are smallest released diameter from (30–100the endosomal nm) and, compartment contrary to of thethe cell above in a EVs, process they arereferred released to fromas exocytosis. the endosomal Briefly, compartment cells generate of the cell exosomes in a process through referred to as exocytosis. Briefly, cells generate exosomes through internal budding from internal budding from the internal surface of intracellular lumen vesicles (ILVs) or en- the internal surface of intracellular lumen vesicles (ILVs) or endosomes. The fusion of dosomes.exosome-containing The fusion of vesicles exosome-containing with the plasma vesicles membrane with results the inplasma exosome membrane release [7 results]. in Releasedexosomeexosomes release [7]. travel Released with the exosomes blood to distant travel organs with andthe interactblood to with distant distant organs cells and interactthrough with a process distant of cells fusion, through interacting a process via surface of fusion, antigens interacting and receptors via surface or through antigens andinternalization receptors or ofthrough the exosome internalization by phagocytosis of the (Figure exosome1). by phagocytosis (Figure 1). FigureFigure 1. Exosome-target 1. Exosome-target cellcell interaction: interaction: (1) membrane (1) membrane fusion allows fusion for allows the transfer for the of bothtransfer the internal of both cargo the moleculesinternal cargo moleculesand membrane and membrane proteins proteins by merging by with merging the plasma with membrane the plasma of a membrane target cell; (2) of junxtacrine a target cell; signaling (2) junxtacrine activates intracellular signaling acti- vates signalingintracellular pathways signaling through pathways ligation ofthrough target cell ligation membrane of ta receptorsrget cell withmembrane exosome receptors membrane with ligands; exosome (3) phagocytosis membrane lig- ands;allows (3) phagocytosis for the internalization allows for of thethe whole internalization exosome by targetof the cell. whole It allows exosome for the by lysosomal target degradationcell. It allows of exosomes.for the lysosomal The degradationbiological
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