Yanwen Wang
Qingfeng Li2*
Shuangbai Zhou- 1Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
- 2Department of Plastic & Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Adipose tissue (AT) serves as an energy-capacitive organ and performs functions involving paracrine- and endocrine-mediated regulation via extracellular vesicles (EVs) secretion. Exosomes, a subtype of EVs, contain various bioactive molecules with regulatory effects, such as nucleic acids, proteins, and lipids. AT-derived exosomes (AT-exos) include exosomes derived from various cells in AT, including adipocytes, adipose-derived stem cells (ADSCs), macrophages, and endothelial cells. This review aimed to comprehensively evaluate the impacts of different AT-exos on the regulation of physiological and pathological processes. The contents and functions of adipocyte-derived exosomes and ADSC-derived exosomes are compared simultaneously, highlighting their similarities and differences. The contents of AT-exos have been shown to exert complex regulatory effects on local inflammation, tumor dynamics, and insulin resistance. Significantly, differences in the cargoes of AT-exos have been observed among diabetes patients, obese individuals, and healthy individuals. These differences could be used to predict the development of diabetes mellitus and as therapeutic targets for improving insulin sensitivity and glucose tolerance. However, further research is needed to elucidate the underlying mechanisms and potential applications of AT-exos.
Graphical Abstract. Adipose tissue comprises a variety of cells, including adipocytes, adipose-derived stem cells, macrophages, fibroblasts, and endothelial cells. These cells produce exosomes that collectively constitute adipose tissue-derived exosomes. These exosomes from adipose tissue are rich in RNA, proteins, lipids, and other components. They have diverse regulatory effects on local inflammation, adipogenesis, tumor progression, and insulin resistance levels. Furthermore, adipose tissue-derived exosomes can impact the physiological and pathological processes of muscles, skin, hypothalamus, and kidneys. (Created with BioRender.com). ADSC, adipose-derived stem cell; miRNA, microRNA; ROS, reactive oxygen species; lnc-BATE1, brown adipose tissue enriched long non-coding RNA 1; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; MALAT1, metastasis-associated lung adenocarcinoma transcript 1.ADSC, adipose-derived stem cell; miRNA, microRNA; ROS, reactive oxygen species; lnc-BATE1, brown adipose tissue enriched long non-coding RNA 1; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; MALAT1, metastasis-associated lung adenocarcinoma transcript 1.
1 Introduction
Adipose tissue (AT) is an important energy storage organ and a vital endocrine organ that regulates the functions of other tissues and organs by secreting various signaling molecules via extracellular vesicles (EVs). These EVs affect neighboring tissues [skin (1) and muscles (2)] and distant organs (heart, lung, liver, and pancreas (3–6)). A study involving 101 patients revealed that 0.2% of serum EVs, which are derived from tissue (7), contain high levels of adipocyte proteins and adipokines (8). AT plays a specific role in the secretion of EVs harboring adipocyte proteins and adipokines, which could have systemic effects on various diseases and physiological processes.
Secretion of EVs is an important mechanism through which cells exert regulatory effects and interact with other cells and organs. EVs are categorized as exosomes, ectosomes, and apoptotic EVs based on their mode of secretion (9); this classification system differs from the previous method of categorizing EVs by size (larger EVs > 200 nm and smaller EVs < 200 nm) (10). Exosomes are formed through the inward budding of the cytomembrane (similar to endocytosis) and organelle membrane, involving the endoplasmic reticulum, Golgi apparatus, and other organelles (11). As a subtype of EVs, exosomes perform primary regulatory and therapeutic functions through their contents, including RNAs (microRNA (miRNA), long noncoding RNA (lncRNA), circular RNA, and mRNA), DNA, proteins, and lipids (12). In addition, mitochondrial components and ceramides have been identified as exosomal cargoes that participate in the regulation of the Wnt and MAPK signaling pathways (13).
AT is composed of various cells, including adipocytes, adipose-derived stem cells (ADSCs), AT macrophages (ATMs), endothelial cells, progenitors, and preadipocytes. Many studies have focused on adipocyte-derived exosomes (adipocyte-exos), ADSC-derived exosomes (ADSC-exos), and ATM-derived exosomes (ATM-exos) and studied the roles of these exosomes separately. Adipocyte-exos account for a major proportion of AT-derived exosomes (AT-exos). Additionally, ADSC-exos have been shown to have meaningful therapeutic effects on multiple diseases (14–17). Extensive evidence has demonstrated that exosomes derived from ADSCs and adipocytes can regulate localized inflammation and metabolic diseases (3, 17), promote wound healing (18, 19), and affect tumor growth and migration (20, 21). However, ADSC-exos are significantly more effective at promoting angiogenesis and protecting the heart and blood vessels than adipocyte-exos. The diameters, different surface features, and major RNAs and lipid components of adipocyte-exos and ADSC-exos are summarized in Figure 1. The majority of proteins in adipocyte-exos are mitochondrial fatty acid oxidase enzymes, such as trifunctional enzyme subunit alpha and hydroxyacyl-coenzyme A dehydrogenase (22). ADSC-exos contain various growth factors and enzymes associated with glycolysis, such as phosphoglucomutase, phosphoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase, enolase, and pyruvate kinase m2 isoform (23), as well as enzymes with dephosphorylation functions (24). Moreover, ATM-exos can play a regulatory role in insulin resistance (25). Furthermore, all of the cells mentioned above produce exosomes, which constitute AT-exos. In summary, AT-exos is complex.
Figure 1. Differences between adipocyte-exos and ADSC-exos. The diameters of the adipocyte-exos were from 30 nm to 200 nm. However, the diameters of the ADSC-exos ranged from 30 nm to 150 nm, with the peak diameters reaching 200 nm. In addition to conventional exosomal markers, both adipocyte-exos and ADSC-exos have unique exosomal markers. The compositions of nucleic acids, proteins, and lipids in the adipocyte-exos and ADSC-exos were also different. FABP4, fatty acid binding protein 4; FAO, fatty acid oxidation; ECHA, trifunctional enzyme subunit alpha; HCDH, hydroxy carboxylic acid dehydrogenase; TSG101, tumor susceptibility gene 101; HSP90, heat shock protein 90; ALIX, ALG-2 interacting protein X; HSPA4, heat shock protein A4; TRAP1, tumor necrosis factor receptor-associated protein 1; HLA-ABC, human leukocyte antigen-ABC.
AT-exos potentially exert regulatory and therapeutic effects on numerous diseases, such as diabetic wounds (19), insulin resistance (26), angiogenesis (27), and nonalcoholic steatohepatitis (28). Different components in AT-exos may regulate the same disease or physiological process in various directions. For different populations, the cargoes delivered by AT-exos and their regulatory effects can vary greatly. For instance, the quantity of AT-exos, especially adipocyte-exos, in obese individuals is significantly increased (29). Moreover, substances within adipocyte-exos, ADSC-exos, and ATM-exos that can alleviate tissue inflammation and mitigate insulin resistance are markedly reduced (30), while those that exacerbate tissue inflammation and worsen insulin resistance are noticeably increased in adipocyte-exos and ATM-exos (31). Consequently, the AT-exos in obese individuals significantly intensify inflammation in local AT and lead to systemic insulin resistance. Because AT-exos is complex, focusing on the effects of AT-exos will provide a more comprehensive and objective understanding than studying one type of cell-derived exosomes in isolation when studying the impact of AT on other tissues and organs.
2 The regulation of inflammation by exosomes derived from AT in the local microenvironment
In the local microenvironment, adipocyte-exos, ADSC-exos, and ATM-exos carry multiple miRNAs and proteins that participate in regulating inflammation. Among these cargoes, some RNAs and proteins can alleviate inflammation, while others can exacerbate inflammation. Notably, the ability of AT-exos to regulate inflammation varies among different populations. AT-exos from obese and aged individuals are more likely to exacerbate inflammation (17, 32).
2.1 The influence of RNAs derived from AT-exos on regulating inflammation
Some RNAs in adipocyte-exos and ADSC-exos can alleviate inflammation in the local microenvironment. Nine adipocyte-exo-derived miRNAs (miR-26a, miR-92a (33), miR-126, miR-143, miR-193a, miR-193b, miR-652, miR-let-7a, and miR-let-7d) can repress the production of C-C motif ligand 2 (CCL2), which induces the polarization of macrophages to the proinflammatory phenotype and is present in higher levels in the serum of obese individuals than in lean individuals (34). miRNAs in ADSC-exos exert a significant effect on inducing M2 macrophage polarization. Activation of NOD-like receptor protein 3 was also proven to be suppressed by ADSC-derived EVs in previous studies (35, 36). In addition, compared to those in old mice, the ADSC-exos in young mice contained higher levels of miR-125b-5p, miR-214-3p, and miR-let7c-5p, which may explain the decreased expression of inflammatory markers and the regeneration of muscle and kidney in old mice injected with ADSC-exos from young mice (17).
AT-exos, including both adipocyte-exos and ADSC-exos, also contain miRNAs that exacerbate inflammation in the AT microenvironment. Moreover, a study confirmed that ADSC-exos also promote macrophage infiltration by upregulating the levels of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α in a fat transfer experiment (37).
2.2 The effects of exosomal proteins and lipids on the regulation of inflammation
The proteins in adipocyte-exos that are implicated in the regulation of inflammation include adipokines (adiponectin, leptin, resistin, and autotaxin), cytokines (interleukin (IL)-6, IL-1β, IL-8, CCL2, CCL5, and TNF-α), and adipsin (38, 39). Among the proteins in adipocyte-exos, adiponectin significantly affects anti-inflammation and is present in higher levels in the AT space and plasma of lean individuals (40). These cytokines in adipocyte-exos have apparent proinflammatory effects (40). For ADSCs, ADSC-exos carry proinflammatory cytokines (IL-1β, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15, IL-17, IFN-γ, and TNF-α) and anti-inflammatory factors (IL-1Ra, IL-4, IL-10, and IL-13) (41), while IL-2, IL-6, and adipsin have both proinflammatory and anti-inflammatory characteristics (42, 43).
Upon the stimulation of M1 polarization, compared with adiponectin-negative EVs, adiponectin-positive EVs derived from adipocytes promote monocyte differentiation into ATM through the secretion of TNF-α, macrophage colony-stimulating factor, and retinol-binding protein 4 (44). A separate study indicated that retinol-binding protein 4 in adipocyte-exos facilitates the M1 polarization of monocytes and the production of proinflammatory cytokines. Furthermore, levels of exosomal retinol-binding protein 4 are elevated in obese mice (30).
The functional RNAs, proteins, and lipids in exosomes derived from AT that regulate the inflammation of the microenvironment are listed in Table 1.
Table 1. RNAs, proteins, and lipids in exosomes derived from AT regulate inflammation.
3 The regulatory effect of exosomes derived from AT on tumors
AT-exos, including adipocyte-exos, ADSC-exos, ATM-exos, endothelial cell-derived exosomes, and exosomes from other AT-derived cells, can affect both adjacent and distant tumor cells. To promote tumor growth, adipocyte-exos can be transported into adjacent tumor cells, such as breast cancer (BC) cells, and improve the proliferation, migration, and chemoresistance of BC cells; this effect is related to stimulating the expression of YAP and TAZ, which are two key downstream proteins of the Hippo signaling pathway (70). In a study on triple-negative BC, cancer-associated adipocytes deliver more C-X-C motif ligand 8 to adjacent BC cells compared to normal adipocytes. C-X-C motif ligand 8 upregulates the expression of the PI3K/AKT/mTOR pathway in tumor cells, promotes the proliferation and epithelial-mesenchymal transition of tumor cells, and enhances the expression of PD-L1 on the BC cell membrane, which is detrimental to the long-term prognosis of patients (71). Fatty acid binding protein 4 derived from adipocyte-exos, expressed at higher levels in metastatic ovarian cancer patients than in primary ovarian cancer patients, is considered a marker of metastatic tumor disease and a therapeutic target (72). Some miRNAs, such as let-7-a-1, miR-21, and miR-1260b, are significantly enriched in ADSC-exos from patients with cancer (73). Moreover, ADSC-exos promote tumor progression by facilitating the proliferation and migration of cancer cells. In comparison to those in the control group, ADSC-exos activates the Wnt signaling pathway in the MCF7 BC cell line and promotes the migration of cancer cells (74). Fewer microvesicles originating from the endothelial cells of BC patients are implicated in better clinical outcomes after chemotherapy (75). Endothelial cell-derived exosomes may also contribute to cancer progression. On the unfavorable aspects of tumors, ADSC-exo-derived miRNAs can suppress tumor growth by increasing the sensitivity of cancer cells to chemotherapy, reducing the expression of drug-resistance genes, promoting cancer cell apoptosis, inhibiting the tumor proliferation and migration, and recruiting natural killer T cells. ADSC-exos can recruit natural killer T cells and promote their antitumor responses in the tumor microenvironment. In an N1S1-induced hepatocellular carcinoma model, mice treated with ADSC-exos had markedly smaller tumor volumes and more circulating and intratumoral natural killer T cells than the control mice (76). In brief, AT-exos can suppress tumor development and promote the proliferation, migration, and drug resistance of tumor cells through the delivery of miRNAs, proteins, and lipids. The contents in various AT-exos affecting tumor progression are summarized in Figure 2. The mechanisms underlying their effects are presented in Table 2.
Figure 2. Adipocyte-exos, ADSC-exos, ATM-exos, and fibroblast-derived exosomes all contain substances that can promote tumor progression by enhancing the proliferation, migration, and chemoresistance of tumor cells. ADSC-exos are rich in various miRNAs that can suppress tumor growth by increasing the sensitivity of tumor cells to chemotherapy drugs, promoting apoptosis, inhibiting proliferation and migration, and recruiting natural killer T cells. (Created with BioRender.com). lncRNA-SNHG1, lncRNA-small nucleolar RNA host gene 1; FABP4, fatty acid binding protein 4; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; CCL2, C-C motif ligand 2; CCL5, C-C motif ligand 5; TNF-α, tumor necrosis factor-α; TSP5, thrombospondin family protein 5; FFA, free fatty acid; lncRNA-HISLA, lncRNA-HIF-1α-stabilizing long noncoding RNA; lncRNA-SNHG3, lncRNA-small nucleolar RNA host gene 3.
Table 2. Effective substances in exosomes derived from AT impact the tumor progression.
4 The effects of exosomes derived from AT on obesity and insulin resistance
As the most important energy storage organ in the human body, AT also performs strong endocrine regulatory functions. AT-exos have been proven to play a regulatory role in the sensitivity of the body to insulin through multiple signaling pathways and are strongly correlated with individual obesity.
Compared to those in healthy and lean individuals, AT-exos in the obese population exhibit significant differences. First, in terms of quantity, the AT of obese individuals and patients with insulin resistance can produce more exosomes (103). Ceramide can promote the membrane curvature of EVs and exert a significant effect on the vesicle budding process. Inhibiting ceramide production can reduce the biogenesis of EVs (104). Moreover, the budding process is influenced by palmitic acid and phospholipase D (105). Obese individuals have a greater variety of ceramides in AT (106) and excessive palmitic acid in enlarged adipocytes (107), which are conducive to the budding of multivesicular bodies in adipocytes, especially in obese individuals. Furthermore, the increased production of exosomes in AT of obese individuals mainly occurs due to increased production by adipocytes, with no significant increase by the other types of cells (108). The number of adipocyte-exos in the circulation of obese mice was approximately twofold higher than that in lean mice (29). Chronic mild inflammation, which is a biological stimulus of AT associated with obesity, might facilitate the secretion of adipocyte-exos (109). However, increased adipocyte-exos could accelerate the excretion of harmful cytoplasmic substances and prevent cellular senescence. The contents and cargoes of adipocyte-exos can also impact other cells and organs throughout the body through paracrine or endocrine effects. The implications of this phenomenon on the human body are intricate and cannot be conclusively defined as beneficial or detrimental. Moreover, the mechanism underlying the increased production of adipocyte-exos in obesity remains incompletely understood (110). The expression profiles of AT-exos, including the levels of miRNAs, proteins, and lipids, also vary between obese individuals and healthy individuals.
4.1 Differentially expressed miRNAs in obese and healthy individuals
As previously mentioned, the following miRNAs are upregulated in the adipocyte-exos of obese individuals: miR-23b, miR-27a, miR-99b, miR-122, miR-140-5p, miR-142-3p, miR-192, miR-222, miR-378a, and miR-4429 (3, 111–114). Moreover, the expression of miR-15a, miR-26a, miR-30c, miR-92a, miR-126, miR-130b, miR-138, miR-143, miR-145, miR-148b, miR-193a, miR-193b, miR-221, miR-223, miR-423-5p, miR-520c-3p, miR-652, miR-4269, miR-let-7af, and miR-let-7d is significantly decreased in the adipocyte-exos of obese individuals (31, 34, 115–119). Among the decreased miRNAs, nine could inhibit the expression of CCL2 to suppress the M1 polarization of macrophages and alleviate inflammation when expressed at higher levels in healthy individuals (34). The influence and working mechanisms of these differential miRNAs are summarized in Table 3.
Table 3. The miRNAs in exosomes derived from AT with different expressions are related to insulin resistance and obesity.
Taken together, these data show that the aberrant expression of these miRNAs in obese individuals could worsen inflammation in AT, leading to obesity. Several plasma miRNAs derived from adipocytes could be considered predictive factors of type 2 diabetes mellitus. For example, increased miR-15b levels and decreased miR-138 levels could be considered characteristic of obese individuals compared with individuals in the normal control group (125, 126). Furthermore, a combined analysis of circulating miR-15a, miR-423-5p, and miR-520c-3p, which are downregulated in obese individuals, could predict whether a man has morbid obesity with an accuracy of up to 93.5% (115).
4.2 Differential levels of proteins and lipids between obese individuals and healthy individuals
Some proteins and lipids derived from AT-exos are also different and associated with inflammation in these two groups. As previously stated, adipocyte-exo derived IL-1β, IL-6, IL-8, CCL2, CCL5, TNF-α (3), resistin, and retinol-binding protein 4 (30) are found to be expressed at higher levels in obese individuals. These proteins are considered to be proinflammatory factors and are associated with insulin resistance, and these proteins can also facilitate the M1 polarization of monocytes (30, 40). Furthermore, macrophage migration inhibitory factor, which is expressed at higher levels in the adipocyte-exos from obese individuals (127), is an upstream regulator of the inflammatory cascade and triggers inflammatory responses via migration inhibitory factor signaling pathways (128). Moreover, the plasma levels of adipsin and neuregulin 4 (Nrg4) are decreased in overweight individuals (129, 130). Nrg4 is shown to protect against type 2 diabetes mellitus and non-alcoholic fatty liver disease because Nrg4 can positively regulate ErbB3 and ErbB4 signaling in hepatocytes and inhibit LXR and SREBP1c, promoting lipogenesis (130). In Nrg4-deficient mice with nonalcoholic steatohepatitis, cell death, inflammation, fibrosis, and liver injury are more serious because Nrg4 can positively regulate ErbB3 and ErbB4 to repress the ubiquitination and proteasomal degradation of c-FLIPL to reduce cell death (131). However, the level of palmitoleate, which has certain anti-inflammatory and insulin-sensitizing effects, is downregulated in obese and insulin-resistant mice (132). The proteins and lipids in adipocyte-exos associated with energy metabolism, lipogenesis, and insulin sensitivity are listed in Table 4. Moreover, the signal transducer and activator of transcription 3 in ADSC-exos can alleviate AT inflammation and promote the beiging of white AT to improve insulin sensitivity and glucose intolerance during high-fat diet consumption (61).
Table 4. Proteins and lipids derived from adipocyte-exos are associated with metabolism and insulin resistance.
In addition to adipocytes and ADSCs, AT is instrumental in regulating the insulin resistance and glucose sensitivity of individuals. In mouse experiments, injecting ATM-exos from obese mice into lean mice decreased insulin sensitivity and induced glucose tolerance. In contrast, ATM-exos obtained from lean mice improved glucose tolerance and insulin sensitivity when administered to obese mice (25, 121). AT contains multiple types of macrophages that secrete different exosomes according to their unique phenotype. Exosomes from M1 macrophages induce insulin resistance in adipocytes, whereas M2 macrophage-derived exosomes improve insulin sensitivity and glucose tolerance (137). IL-4 derived from THP-1 macrophages can decrease miR-33 expression and upregulate miR-21, miR-99a, miR-146b, and miR-378a in both adipocytes and macrophages to promote lipophagy and oxidative phosphorylation, and these effects are accompanied by enhanced insulin sensitivity (138). High expression of glypican-4 in preadipocytes can result in insulin resistance in the initial stage of obesity (139). Additionally, the increased expression of short stature homeobox 2, which is linked to imbalanced fat storage in subcutaneous adipocytes compared to visceral adipocytes (140), can decrease the expression of the β3 adrenergic receptor, leading to reduce lipolysis (141). According to the findings of these studies, subcutaneous preadipocytes in the obese population can promote more proliferation and accumulation of AT. The cargoes in AT-exos associated with insulin resistance are recapitulated in Figure 3.
Figure 3. The properties of AT-exos from the obese population and the contents in AT-exos derived from obese individuals are related to the exacerbation of insulin resistance. With an increased quantity, the adipocyte-exos of obese individuals exhibit significant alterations compared to those of normal individuals. The upregulation of certain microRNAs and proteins within these exosomes can exacerbate insulin resistance. Conversely, the downregulation of various RNAs, proteins, and lipid can alleviate insulin resistance, thereby significantly worsening the insulin resistance in obese individuals. Exosomes from ADSCs and macrophages also contain substances that can regulate insulin resistance levels. miR-155 from ATM-exos can inhibit adipogenesis and reduce insulin secretion from pancreatic β cells, aggravating insulin resistance. (Created with BioRender.com). miR-126, miR-223, and STAT3 in ADSC-exos, as well as IL-4 from ATM-exos, are associated with the reduction of inflammation, thereby alleviating insulin resistance. IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; CCL2, C-C motif ligand 2; CCL5, C-C motif ligand 5; TNF-α, tumor necrosis factor-α; RBP4, retinol binding protein 4; FAHFAs, fatty acid ester of hydroxy fatty acids; FABP4, fatty acid binding protein 4; FGF21, fibroblast growth factor 21; STAT3, signal transducer and activator of transcription 3; IL-1β, interleukin-1β.
The modulatory influences of adipocyte-exos, ADSC-exos, and ATM-exos on inflammation, tumor progression, and insulin resistance are concisely detailed in Table 5.
Table 5. Brief overview of adipocyte-exos, ADSC-exos, and ATM-exos regulating inflammation, tumor progression, and insulin resistance.
5 The regulating action of exosomes derived from AT on other tissues and organs
In addition to affecting inflammation, tumors, and insulin resistance, AT can also have regulatory functions on adipocytes themselves, muscle, skin, hypothalamus, and kidney through the delivery of exosomes in the progression of adipogenesis, myodystrophy, skin photoaging, appetite, and renal fibrosis. AT exosomal RNAs play a crucial role in the regulation of adipogenesis (142, 143) and the transformation between white adipocytes and brown adipocytes, such as miR-92a, miR-155, miR-193b, miR-196a, miR-337, and miR-455 (144). Knockout of Dicer, the miRNA-processing enzyme, causes lipodystrophy of visceral and subcutaneous adipocytes, serious insulin resistance, and ‘whitening’ of brown adipocytes in the mouse scapular region (145, 146). Adipocyte-exos could deliver miRNAs to skeletal muscle cells, regulating the metabolism and differentiation of muscle cells. The contents of AT-exos in myodystrophy patients are also different from those in normal individuals (2, 147, 148). Numerous studies have shown that ADSC-exos are beneficial to inflammation-related diseases, which has been confirmed in skin photoaging and renal fibrosis (149, 150). The effective RNAs in AT-exos are listed in Table 6.
Table 6. AT-exos influence other tissues or organs in diseases or physiological processes.
Meanwhile, the proteins and lipids in AT-exos also act as regulators in the physiological and pathological processes. Proteins in adipocyte-exos, known as exoadipokines, are associated with inflammation and fibrosis, affect on signaling pathways, and membrane proteins (157). The proteins in both adipocyte-exos and ADSC-exos, as cargoes, can be categorized into regulatory factors and metabolism-related enzymes (110, 158). The enzymes in ADSC-exos can convert adenosine monophosphate to adenosine to activate the PI3K/Akt pathway, exerting a protective effect on myocarditis and arrhythmias (159). Additionally, in tissue infections, ADSCs release the antibacterial peptides and proteins, such as antibacterial peptide LL-37, hepcidin, β-defensin-2, and lipocalin-2, which inhibit the synthesis of DNA, RNA, and valid proteins in infected cells to facilitate the cell-killing process and restore the balance of infection and inflammation (160–162). Lipids in exosomes also play a role in inducing the differentiation of immune cells and regulating gene expression. Lipids in adipocyte-exos promote the differentiation of monocytes from bone marrow into ATM (29). ADSC-exos contain various bioactive lipids, including monounsaturated fatty acids, polyunsaturated fatty acids, and multiple saturated fatty acids. These fatty acids, such as arachidonic acid, prostaglandins, lysophosphatidylcholine, leukotrienes, phosphatidic acid, and docosahexaenoic acid (133), facilitate the transmission of information between cells through different signaling pathways. Arachidonic acid, a common ω-6 polyunsaturated fatty acid, participates in the biosynthesis of prostaglandin. The prostaglandin E2-EP3, found in bone marrow mesenchymal stem cells with selective secretion (163), can induce acute inflammation performance (164). Furthermore, prostaglandin E2 can also accelerate tumor cell proliferation (165). In clinical trials, high expression of docosahexaenoic acid is related to better chemotherapy effect in BC and non-small-cell lung cancer patients (166).
6 Clinical implications of AT-exos
Exosomes, which are characterized by low immunogenicity, regulate recipient cells by delivering cargoes to achieve cell-free therapy. Both utilizing the substances contained in exosomes and delivering drugs through exosomes are beneficial methods for disease treatment. AT-exos were proven to be therapeutic for wound healing by promoting the proliferation and migration of fibroblasts and HaCaT cells as well as angiogenesis (19). AT-exo-derived lnc-H19 (167) and miR-221-3p (27) can promote cell proliferation and vascularization, respectively. Furthermore, AT-exos have potential therapeutic benefits for liver injury, cardiac fibrosis, metabolic syndrome, and tumors (168, 169). As mentioned above, AT-exos are present at different levels in obese and diabetic people than in healthy people and could serve as a basis for identifying potentially diabetic patients from healthy or obese people.
However, there are several limitations in the clinical application of AT-exos. First, the stability of AT-exos during storage is challenging because exosomes are susceptible to environmental conditions during storage and degrade over time, which limits their long-term storage and wide application. Moreover, there is no consensus about preparation methods and quality control standards of AT-exos, which leads to uncertainty about the quality and efficacy of exosomes, limiting their reliability and reproducibility in clinical application. Finally, although AT-exos are considered relatively safe, they have potential safety concerns and side effects, such as immune responses or other adverse reactions. The safety, dosage, and treatment options of AT-exos need to be further studied and evaluated in additional animal and clinical experiments.
Compared with AT-exos, ADSC-exos have been extensively studied in clinical applications, and they have strong and wide-ranging impacts. In addition to promoting cell proliferation and migration as well as angiogenesis in wound healing (170), ADSC-exos have great curative effects on inflammation-related diseases (Crohn’s disease, idiopathic pulmonary fibrosis, COVID-19, arthritis, autoimmune diabetes, etc.), myocardial ischemia, and delayed photoaging (3, 150, 160, 171). Unlike ADSC-exos, some studies have shown that AT-exos in obese people could increase inflammation and exacerbate disease (172, 173). So, the efficacy of AT-exos from obese people in the treatment of inflammatory diseases is still controversial. Ultimately, compared with ADSC-exos, AT-exos have great advantages in terms of preparation. AT-exos are directly extracted from AT without the need for cell expansion, meaning that the time required for AT-exo preparation is significantly shorter than that required for ADSC-exo preparation. AT-exos, which are exosomes in mature tissue, are significantly more abundant than ADSC-exos produced by primary ADSCs that are extracted from the same volume of AT.
7 Conclusions and prospects
AT-exos, which are produced by various AT cells, mediate paracrine and endocrine regulation of the local microenvironment and distant organs by delivering nucleic acids, proteins, and lipids. Among AT-exos, adipocyte-exos and ADSC-exos have positive impacts on wound healing and cardiovascular protection, while their regulatory effects on inflammation and tumors are complicated. Furthermore, the contents of AT-exos significantly differ among healthy individuals, obese individuals, and diabetic patients. These differences could serve as targets for identifying patients with early-stage diabetes. Modulating the expression of insulin-related genes may improve the insulin sensitivity of patients and contribute to the treatment of diabetes and obesity.
Various cells within AT generate exosomes that perform diverse regulatory functions. Considering AT-exos as a whole is valuable for studying the regulatory effect of AT on other organs in the body. In order to better understand the regulatory role of AT-exos and take advantage of AT-exos, further studies could focus on the following directions: (1) Identifying appropriate patients with inflammation-related diseases for treatment with autologous AT-exos due to their complex regulatory effects of AT-exos on inflammation. (2) Investigating whether AT-exos exacerbate tumor progression and increase the risk of recurrence in BC patients with fat breast augmentation after resection. (3) contents, such as miRNAs, proteins, and lipids, in AT-exos can be used to predict whether obese patients will suffer from diabetes, although the expression of miRNAs is easily affected by stimulation. (4) Enhancing the separation and purification techniques of exosomes from various cellular sources to facilitate the development of targeted therapies and achieve desired treatment outcomes. (5) Improving methods for the preparation and storage of AT-exos to ensure uniformity, which will greatly enhance the clinical application of AT-exos. Addressing these key questions will pave the way for the development and more efficient use of autologous AT-exos for treating diseases in clinical practice.
Author contributions
YW: Conceptualization, Writing – original draft. QL: Writing – review & editing, Funding acquisition, Supervision. SZ: Funding acquisition, Supervision, Writing – review & editing. PT: Supervision, Writing – review & editing.
Funding
The authors declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants from the National Natural Science Foundation of China (82272287); Cross-disciplinary Research Fund of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYJC202215); Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by Science and Technology Commission of Shanghai Municipality (Grant No. 22MC1940300); project list of “National Double First-Class” and “Shanghai-Top-Level” high education initiative at Shanghai Jiao Tong University School of Medicine.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: adipose tissue, adipose-derived stem cell (ADSC), exosome, inflammation, tumor, diabetes
Citation: Wang Y, Li Q, Zhou S and Tan P (2024) Contents of exosomes derived from adipose tissue and their regulation on inflammation, tumors, and diabetes. Front. Endocrinol. 15:1374715. doi: 10.3389/fendo.2024.1374715
Received: 24 January 2024; Accepted: 31 July 2024;
Published: 16 August 2024.
Edited by:
Marcia Hiriart, Universidad Nacional Autonoma de Mexico, MexicoReviewed by:
Zhiqiang Huang, Nanjing University, ChinaXiaosong Chen, Fujian Medical University Union Hospital, China
Copyright © 2024 Wang, Li, Zhou and Tan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Qingfeng Li, dr.liqingfeng@yahoo.com; Shuangbai Zhou, shuangbaizhou@yahoo.com; Pohching Tan, bojun_tan@hotmail.com