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

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.

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Fed-EXosome: extracellular vesicles and cell–cell communication in metabolic regulation

Essays in Biochemistry ◽

10.1042/ebc20170087 ◽

2018 ◽

Vol 62 (2) ◽

pp. 165-175 ◽

Cited By ~ 16

Author(s):

Isabella Samuelson ◽

Antonio J. Vidal-Puig

Keyword(s):

Extracellular Vesicles ◽

Cross Talk ◽

Metabolic Regulation ◽

Metabolic Diseases ◽

Whole Body ◽

Target Cells ◽

Metabolic Complications ◽

Obesity And Diabetes ◽

Lipid Species ◽

Cell Cell

Extracellular vesicles (EVs) have emerged as a novel messaging system of the organism, mediating cell–cell and interorgan communication. Through their content of proteins and nucleic acids, as well as membrane proteins and lipid species, EVs can interact with and modulate the function of their target cells. The regulation of whole-body metabolism requires cross-talk between key metabolic tissues including adipose tissue (AT), the liver and skeletal muscle. Furthermore, the regulation of nutrient/energy allocation during pregnancy requires co-ordinated communication between the foetus and metabolic organs of the mother. A growing body of evidence is suggesting that EVs play a role in communication between and within key metabolic organs, both physiologically during metabolic homoeostasis but also contributing to pathophysiology during metabolic dysregulation observed in metabolic diseases such as obesity and diabetes. As obesity and its associated metabolic complications are reaching epidemic proportions, characterization of EV-mediated communication between key metabolic tissues may offer important insights into the regulation of metabolic functions during disease and offer global therapeutic opportunities. Here, we focus on the role of EVs in metabolic regulation and, in particular, EV-mediated cross-talk between cells of the AT.

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Extracellular Vesicles from Adipose Tissue Stem Cells in Diabetes and Associated Cardiovascular Disease; Pathobiological Impact and Therapeutic Potential

International Journal of Molecular Sciences ◽

10.3390/ijms21249598 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9598

Author(s):

Alina Constantin ◽

Alexandru Filippi ◽

Nicoleta Alexandru ◽

Miruna Nemecz ◽

Adriana Georgescu

Keyword(s):

Cardiovascular Disease ◽

Stem Cells ◽

Adipose Tissue ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Bioactive Molecules ◽

Target Cells ◽

Long Distance ◽

Differentiation Potential ◽

Cardiovascular Tissue

Adipose tissue-derived stem cells (ADSCs) are pluripotent mesenchymal stem cells found in relatively high percentages in the adipose tissue and able to self-renew and differentiate into many different types of cells. “Extracellular vesicles (EVs), small membrane vesicular structures released during cell activation, senescence, or apoptosis, act as mediators for long distance communication between cells, transferring their specific bioactive molecules into host target cells”. There is a general consensus on how to define and isolate ADSCs, however, multiple separation and characterization protocols are being used in the present which complicate the results’ integration in a single theory on ADSCs’ and their derived factors’ way of action. Metabolic syndrome and type 2 diabetes mellitus (T2DM) are mainly caused by abnormal adipose tissue size, distribution and metabolism and so ADSCs and their secretory factors such as EVs are currently investigated as therapeutics in these diseases. Moreover, due to their relatively easy isolation and propagation in culture and their differentiation ability, ADSCs are being employed in preclinical studies of implantable devices or prosthetics. This review aims to provide a comprehensive summary of the current knowledge on EVs secreted from ADSCs both as diagnostic biomarkers and therapeutics in diabetes and associated cardiovascular disease, the molecular mechanisms involved, as well as on the use of ADSC differentiation potential in cardiovascular tissue repair and prostheses.

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Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042213 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2213

Author(s):

Natalia Diaz-Garrido ◽

Cecilia Cordero ◽

Yenifer Olivo-Martinez ◽

Josefa Badia ◽

Laura Baldomà

Keyword(s):

Extracellular Vesicles ◽

Intestinal Mucosa ◽

Current Knowledge ◽

Cell Communication ◽

Bioactive Molecules ◽

Target Cells ◽

Immune Functions ◽

Intestinal Homeostasis ◽

General Terms ◽

Health And Disease

Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.

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Inflammation and impaired adipogenesis in hypertrophic obesity in man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E999-E1003 ◽

Cited By ~ 162

Author(s):

Birgit Gustafson ◽

Silvia Gogg ◽

Shahram Hedjazifar ◽

Lachmi Jenndahl ◽

Ann Hammarstedt ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Molecular Mechanisms ◽

Whole Body ◽

Preadipocyte Differentiation ◽

Metabolic Complications ◽

Adipose Cell ◽

Subcutaneous Adipose ◽

Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

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Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

Biomolecules ◽

10.3390/biom10091327 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1327 ◽

Cited By ~ 1

Author(s):

Loredana Leggio ◽

Greta Paternò ◽

Silvia Vivarelli ◽

Francesca L’Episcopo ◽

Cataldo Tirolo ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Bioactive Molecules ◽

Substantia Nigra Pars Compacta ◽

Diagnostic Tools ◽

Target Cells ◽

Small Interfering Rnas ◽

Wide Range ◽

Ligand Interactions ◽

The Central Nervous System

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

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The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

Nature Communications ◽

10.1038/s41467-019-12661-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Subramanya Srikantan ◽

Yilun Deng ◽

Zi-Ming Cheng ◽

Anqi Luo ◽

Yuejuan Qin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tumor Suppressor ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Suppressor Gene ◽

Nutrient Sensing ◽

Whole Body ◽

Insulin Sensitizer

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

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Extracellular Vesicles as Biological Shuttles for Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms20081848 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1848 ◽

Cited By ~ 20

Author(s):

Stefania Raimondo ◽

Gianluca Giavaresi ◽

Aurelio Lorico ◽

Riccardo Alessandro

Keyword(s):

Extracellular Vesicles ◽

Therapeutic Agents ◽

Bioactive Molecules ◽

Target Cells ◽

Special Focus ◽

Pathological Conditions ◽

Critical Issues ◽

Membrane Bound ◽

And Function ◽

Potential Use

The development of effective nanosystems for drug delivery represents a key challenge for the improvement of most current anticancer therapies. Recent progress in the understanding of structure and function of extracellular vesicles (EVs)—specialized membrane-bound nanocarriers for intercellular communication—suggests that they might also serve as optimal delivery systems of therapeutics. In addition to carrying proteins, lipids, DNA and different forms of RNAs, EVs can be engineered to deliver specific bioactive molecules to target cells. Exploitation of their molecular composition and physical properties, together with improvement in bio-techniques to modify their content are critical issues to target them to specific cells/tissues/organs. Here, we will discuss the current developments in the field of animal and plant-derived EVs toward their potential use for delivery of therapeutic agents in different pathological conditions, with a special focus on cancer.

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Whole-body skeletal muscle mass is not related to glucose tolerance or insulin sensitivity in overweight and obese men and women

Applied Physiology Nutrition and Metabolism ◽

10.1139/h08-060 ◽

2008 ◽

Vol 33 (4) ◽

pp. 769-774 ◽

Cited By ~ 32

Author(s):

Jennifer L. Kuk ◽

Katherine Kilpatrick ◽

Lance E. Davidson ◽

Robert Hudson ◽

Robert Ross

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Muscle Mass ◽

Visceral Adipose Tissue ◽

Skeletal Muscle Mass ◽

Whole Body ◽

Men And Women ◽

Visceral Adipose

The relationship between skeletal muscle mass, visceral adipose tissue, insulin sensitivity, and glucose tolerance was examined in 214 overweight or obese, but otherwise healthy, men (n = 98) and women (n = 116) who participated in various exercise and (or) weight-loss intervention studies. Subjects had a 75 g oral glucose tolerance test and (or) insulin sensitivity measures by a 3 h hyperinsulinemic–euglycemic clamp technique. Whole-body skeletal muscle mass and visceral adipose tissue were measured using a multi-slice magnetic resonance imaging protocol. Total body skeletal muscle mass was not associated with any measure of glucose metabolism in men or women (p > 0.10). These observations remained independent of age and total adiposity. Conversely, visceral adipose tissue was a significant predictor of various measures of glucose metabolism in both men and women with or without control for age and (or) total body fat (p < 0.05). Although skeletal muscle is a primary site for glucose uptake and deposition, these findings suggest that unlike visceral adipose tissue, whole-body skeletal muscle mass per se is not associated with either glucose tolerance or insulin sensitivity in overweight and obese men and women.

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Activated Ask1-MKK4-p38MAPK/JNK Stress Signaling Pathway in Human Omental Fat Tissue May Link Macrophage Infiltration to Whole-Body Insulin Sensitivity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0002 ◽

2009 ◽

Vol 94 (7) ◽

pp. 2507-2515 ◽

Cited By ~ 61

Author(s):

Matthias Blüher ◽

Nava Bashan ◽

Iris Shai ◽

Ilana Harman-Boehm ◽

Tanya Tarnovscki ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Fat Distribution ◽

Macrophage Infiltration ◽

Whole Body ◽

Strongly Correlated ◽

Jnk Pathway ◽

Paired Samples ◽

Adipocyte Cell ◽

Stress Sensing

Context: Adipose tissue in obesity is thought to be exposed to various stresses, predominantly in intraabdominal depots. We recently reported that p38MAPK and Jun N-terminal kinase (JNK), but not ERK and inhibitory-κB kinase β, are more highly expressed and activated in human omental (OM) adipose tissue in obesity. Objective: The aim was to investigate upstream components of the pathways that culminate in activation of p38MAPK and JNK. Setting and Patients: Phosphorylation and expression of kinases were studied in paired samples of OM and sc adipose tissue from lean and obese subjects of two different cohorts (n = 36 and n = 196) by Western and real-time PCR analyses. The association with fat distribution, macrophage infiltration, insulin sensitivity, and glucose metabolism was assessed by correlation analyses. Results: The amount of phosphorylated forms of the kinases provided evidence for an activated stress-sensing pathway consisting of the MAP3K Ask1 (but not MLK3 or Tak1), and the MAP2Ks MKK4, 3/6, (but not MKK7), specifically in OM. OM Ask1-mRNA was more highly expressed in predominantly intraabdominally obese persons and most strongly correlated with estimated visceral fat. Diabetes was associated with higher OM Ask1-mRNA only in the lean group. In OM, macrophage infiltration strongly correlated with Ask1-mRNA, but the obesity-associated increase in Ask1-mRNA could largely be attributed to the adipocyte cell fraction. Finally, multivariate regression analyses revealed OM-Ask1 as an independent predictor of whole-body glucose uptake in euglycemic-hyperinsulinemic clamps. Conclusions: An Ask1-MKK4-p38MAPK/JNK pathway reflects adipocyte stress associated with adipose tissue inflammation, linking visceral adiposity to whole-body insulin resistance in obesity.

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Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes

10.2337/figshare.12315737.v1 ◽

2020 ◽

Author(s):

Oana P. Zaharia ◽

Klaus Strassburger ◽

Birgit Knebel ◽

Yuliya Kupriyanova ◽

Yanislava Karusheva ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Lipid Content ◽

Whole Body ◽

Hepatic Lipid ◽

Insulin Resistant ◽

Increased Risk ◽

Glucose Tolerant ◽

Hepatic Lipid Content

<a>Objective</a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. Research Design and Methods: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. Results: The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001). Conclusions: Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

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