Contents of exosomes derived from adipose tissue and their regulation on inflammation, tumors, and diabetes

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.


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)(4)(5)(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, adiposederived 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.
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.

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).
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-1a in a fat transfer experiment (37).
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-a, 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 p o l a r i z a t i o n o f m o n o c y t e s a n d t h e p r o d u c t i o n o f 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.
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 ATderived 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 adipocyteexos, 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.

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

Substances Derived Function
Mechanisms References (54) miR-34a Adipocyte Aggravate inflammation miR-34a represses the expression of KLF4 to decrease the differentiation of macrophages to M2 polarization.Furthermore, miR-34a in VAT is enriched selectively more than that in the SAT, with a higher expression of miR-34a in VAT after feeding on the HFD.The greater enrichment of miR-34a in VAT can potentially elucidate why VAT is more susceptible to inflammation compared to SAT.
(2) Adiponectin reduces the production of ROS via the NADPH oxidase and suppresses the activity of TNF-a in the macrophages.
(3) Adiponectin can decrease the chemokine CXCL8 production in the peripheral blood neutrophils.
(4) Adiponectin promotes the formation of APPL1/leptin complex, activating TCF/LEF and Wnt/ b-catenin signaling to upregulate the expression of CD44 in the vascular tissue.(67-69) 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 Leptin Adipocyte Leptin targets the Ob-R/LEPR receptor on the cancer cell surface to enhance the expression of PLOD2 and activates signaling pathways, such as JAK/STAT3 and PI3K/AKT signaling pathways, as well as the adipocyte-derived IL-6.Leptin contributes to the maintenance of androgen phenotype in BC, the cancer cell proliferation, and the EMT in ovarian cancer cells.
(89-91) Lipid FFA Adipocyte FFA supplies energy, affects biosynthesis, and regulates the endocrine system.FFA can also activate the PPARa signaling pathway to upregulate the expression of catabolic enzymes in hepatocytes and accelerate the progress of FAO in the mitochondria to enhance cancer cell migration in melanoma cells.(22,92) Lactic acid and glutamic acid Bone marrow mesenchymal stem cell Lactic acid and glutamic acid are the energy-supplying substance and the raw material for substance synthesis, respectively.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.
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).

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-1b, IL-6, IL-8, CCL2, CCL5, TNF-a (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.

Substance Mechanisms Reference
Proteins Adipsin Complement factor C3a, whose generation depends on adipsin level, can bind with the C3a receptor and activate the Ca 2+ signaling pathway in pancreatic b cells, thereby accelerating insulin secretion.Obese individuals and T2DM patients exhibit lower circulating adipsin levels, which is thought of as a monitoring factor for patients in the prediabetic state.
Mitochondrial FAO enzymes ECHA and HCDH Adipocytes can provide FAO enzymes, fatty acids, and various autophagic proteins to melanoma cells for energy supply and lipophagy.
FABP4 FABP can promote the progression of the obesity-related diseases and combine with AA to form the FABP-AA complex.This complex targets the PPARg receptor and regulates the target gene transcription in the cell nucleus.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 b3 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 ATexos associated with insulin resistance are recapitulated in Figure 3.
The modulatory influences of adipocyte-exos, ADSC-exos, and ATM-exos on inflammation, tumor progression, and insulin resistance are concisely detailed in Table 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 miRNAprocessing 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 ATexos are listed in Table 6.
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, b-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)(161)(162).Lipids in exosomes also play a role in inducing the differentiation of immune cells and regulating gene expression.Lipids in adipocyteexos 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 Runx1t1, runt related transcription factor 1 partner transcriptional co-repressor 1; lnc-BATE1, brown adipose tissue enriched long non-coding RNA 1; BAT, brown adipose tissue; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; AP-1, activator protein-1; MMP1, matrix metalloproteinase 1; TGF-b, transforming growth factor b.
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 w-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).

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-exoderived lnc-H19 (167) and miR-221-3p ( 27) can promote cell proliferation and vascularization, respectively.Furthermore, ATexos 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 wideranging impacts.In addition to promoting cell proliferation and migration as well as angiogenesis in wound healing (170), ADSCexos 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 ADSCexos, AT-exos have great advantages in terms of preparation.ATexos 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 ADSCexo 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.

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 ATexos 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.

FIGURE 1
FIGURE 1 binds with the TRADD mRNA and silences TRADD to reduce the expression of inflammatory factors in endothelial cells and prevent the apoptosis of endothelial cells.-5p binds to the 3′-untranslated region of TXNIP and decreases the expression of the TXNIP-NLRP3 signaling pathway in the macrophages.-3p binds to the CSF-1 mRNA to inhibit its translation, causing the polarization of monocytes to M2 macrophages and alleviating inflammation.targets macrophage migration inhibitory factor to promote the M2 polarization and relieve the inflammation in bone healing.targets TRAF6, the transducer of the NF-kB pathway, and inhibits the NF-kB signal to suppress the M1 macrophage polarization.targets and reduces NLRP3, an important component of the inflammasome, to relieve the severity of inflammation.targets SOCS1 and induces M1-polarization by activating the expression of STAT1 and inhibiting STAT6 expression.
adiponectin receptor agonist, reduces the expression of pro-inflammatory cytokines in LPS-induced macrophages, with the effect on myeloid differentiation marker 88 signaling to attenuate the association of the adiponectin receptors and inhibits the activation of NF-kB, MAPK, and c-Maf pathways.can attenuate STAT3/NF-kB signal in adipocytes and induce the M2 polarization.transcription of arginase-1 to promote M2 macrophage polarization after internalizing in macrophages.eicosatetraenoic acid inhibits macrophage-mediated pro-inflammatory reactions and alleviates the cardiac fibroblasts.production and inhibits the migration of the neutrophils.Leptin can increase the expression of inflammatory factors (IL-2, IL-12, and IFN-g) in monocytes to induce a Th1-dominant immune response in infection.LPA receptors to stimulate multiple G-protein mediated signal transduction pathways, including the Enpp2 gene, Ras/Raf/MEK/ERK pathway, and PI3K signaling pathway, and causes more inflammation in fibroblasts, epithelial cells, and endothelial cells, resulting in higher levels of IL-8 and TNF-b to aggravate the tissue fibrosis.and IL-1b repress the adipogenesis of ADSC and combine with IFN-g to promote the immunosuppressive properties of ADSC by excreting more indoleamine 2,3-dioxide in humans or more iNOS in mice.exacerbates insulin resistance and inflammatory metabolic diseases in adipocytes, hepatocytes, myocytes, endothelial cells, and other cells by influencing the pattern recognition receptor TLR4.

( 93 )
Suppress tumor development.(Allthe following miRNAs were derived from ADSC-exo) targets and silences b-catenin to promote radiation-induced apoptosis in NPC cells.miR-34c inhibits the malignant behavior of NPC, such as proliferation, migration, invasion, and epithelialinhibits the expression of target genes CCNG1, ADAM10, and IGF1R, and increases the sensitization of HCC to 5-FU and sorafenib.(95)miR-124and miR-145 miR-124 and miR-145 inhibit the migration of glioma cells and self-renewal of glioma stem cells by targeting SCP-1 and SOX2, relatively.miR-124-3p is reported to suppress glioma proliferation through the FLOT2/AKT1 pathway.miR-145 can reduce the activity of Bcl-X(L) in prostate cancer cells, thereby suppressing cell proliferation and promoting tumor apoptosis.
the hypothalamic-pituitary-adrenal axis to promote liver gluconeogenesis, ketogenesis, and fatty acid oxidation during fasting.FGF21 in AT-exos can increase heat production and accelerate the development of beige adipocytes under cold stimulation.And the BAT-derived FGF21 has an endocrine regulatory function to reduce cardiac hypertrophy.(134,135)LipidsFAHFAs FAHFAs can target G-protein-coupled receptors 40 and 120 to promote insulin secretion and relieve insulin resistance, with decreased levels in obese individuals.(43,136)T2DM, type 2 diabetes mellitus; FAO, fatty acid oxidation; ECHA, trifunctional enzyme subunit alpha; HCDH, hydroxy carboxylic acid dehydrogenase; AA, arachidonic acid; FGF21, fibroblast growth factor 21; BAT, brown adipose tissue; FAHFA, fatty acid ester of hydroxy fatty acid.

FIGURE 3
FIGURE 3The 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 b 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-1b, interleukin-1b; IL-6, interleukin-6; IL-8, interleukin-8; CCL2, C-C motif ligand 2; CCL5, C-C motif ligand 5; TNF-a, tumor necrosis factor-a; 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-1b, interleukin-1b.

TABLE 1
RNAs, proteins, and lipids in exosomes derived from AT regulate inflammation.

TABLE 2
Effective substances in exosomes derived from AT impact the tumor progression.These two lncRNAs are abundant in MM cells and develop the chemoresistance of MM cells.And MM cells can improve the levels of these two lncRNAs in adipocyte-exo by methyltransferases such as 7A which is an RNA methyltransferase and mediates lncRNA m 6 A methylation.This process results in a loop to enhance the resistance of MM cells to chemotherapy between MM cells and MMassociated adipocytes.

TABLE 3
The miRNAs in exosomes derived from AT with different expressions are related to insulin resistance and obesity.

TABLE 6
AT-exos influence other tissues or organs in diseases or physiological processes.