Adipose Extracellular Vesicles in Intercellular and Inter-Organ Crosstalk in Metabolic Health and Diseases

Abstract

Adipose tissue (AT) is a highly heterogeneous and dynamic organ that plays important roles in regulating energy metabolism and insulin sensitivity. In addition to its classical roles in nutrient sensing and energy storage/dissipation, AT secretes a large number of bioactive molecules (termed adipokines) participating in immune responses and metabolic regulation through their paracrine and/or endocrine actions. Adipose-derived extracellular vesicles (ADEVs), including exosomes, microvesicles (MVs), and apoptotic bodies, have recently emerged as a novel class of signal messengers, mediating intercellular communications and inter-organ crosstalk. In AT, ADEVs derived from adipocytes, immune cells, mesenchymal stem cells, endothelial cells are actively involved in modulation of immune microenvironment, adipogenesis, browing of white adipose tissue, adipokine release and tissue remodeling. Furthermore, ADEVs exert their metabolic actions in distal organs (such as liver, skeletal muscle, pancreas and brain) by sending genetic information (mainly in the form of microRNAs) to their target cells for regulation of gene expression. Here, we provide an updated summary on the nature and composition of ADEVs, and their pathophysiological functions in regulating immune responses, whole-body insulin sensitivity and metabolism. Furthermore, we highlight the latest clinical evidence supporting aberrant production and/or function of ADEVs as a contributor to obesity-related chronic inflammation and metabolic complications and discuss the opportunities and challenges in developing novel therapies by targeting ADEVs.

Keywords: adipose tissue macrophage; cell-cell communication; exosome; inflammation; metabolic homeostasis; microRNA.

Figure 1

ADEVs-mediated intercellular communication in adipose tissue. Adipocytes mediate the polarization and immunomodulatory responses of adipose-resident macrophages (ATMs) in a paracrine manner via various vesicular components. ATMs reciprocally regulate adipocyte insulin sensitivity by releasing miRNA-containing EVs to adipocytes. Adipocytes also delivery exosomal proteins to neighboring preadipocytes and adipocytes in both a paracrine and an autocrine manner, respectively, to modulate lipogenesis. Adipose-derived stem cells (ADSCs) confer EV-mediated paracrine effects on both adipocytes and ATMs to regulate adipocyte reprogramming and macrophage polarization, respectively. Endothelial cells in adipose tissue transfer EVs containing proteins and lipids capable of modulating cellular signaling pathways to adipocytes. ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; G6PD, glucose-6-phosphate dehydrogenase; PPARγ, peroxisome proliferator activated receptor gamma; RBP4, retinol binding protein 4; α-KG, α-ketoglutarate; SOCS1, suppressor of cytokine signaling 1; KLF4, krüppel-like factor 4; STAT3, signal transducer and activator of transcription 3; NF-κB, nuclear factor kappa B; ARG1, arginase 1.

Figure 2

ADEVs-mediated interorgan crosstalk in metabolic regulation. Both white and brown adipose tissues secrete EVs containing various types of vesicular components into the circulation. The ADEVs can act as endocrine factors affecting metabolic profiles in distal organs by sending bioactive vesicular molecules. In the liver, exosomal miRNAs modulate glucose tolerance and insulin sensitivity through modulation of peroxisome proliferator activated receptor gamma (PPARγ) and perhaps fibroblast growth factor 21 (FGF21). In skeletal muscle, miRNAs regulate insulin sensitivity and lipid oxidative capacity through PPARγ and PPARγ coactivator 1α (PGC1α), respectively. In pancreas, ADEV-derived miRNAs modulate β-cell mass and insulin secretion. In brain, ADEVs-derived long non-coding RNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) regulates mTOR signaling in hypothalamic pro-opiomelanocortin (POMC) neurons to control appetite and body weight. In the bloodstream, exosomal proteins and lipids affect the differentiation and immunomodulatory responses of monocytes. RBP4, retinol binding protein 4; WAT, white adipose tissue; BAT, brown adipose tissue; MAFB, v-maf musculoaponeurotic fibrosarcoma oncogene family protein B.