Role of adipocytes and their derived extracellular vesicles in the progression, diagnosis and treatment of liver diseases (Review)

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  Figure 1. Differentiation and distribution of adipocytes. Adipocyte differentiation begins with MSCs that commit to either the white or brown lineage. White adipocytes arise from Myf5-negative progenitor cells, whereas brown adipocytes originate from Myf5-positive progenitors. Beige adipocytes are derived from white adipocytes through a process termed 'browning', typically induced by stimuli, such as cold exposure or β-adrenergic activation. White adipose tissue is predominantly located in the omentum, mesentery and subcutaneous depots, while brown adipose tissue is found in the neck, supraclavicular region, mediastinum, paravertebral region, and adrenal areas. Arrows indicate differentiation or conversion pathways. MSCs, mesenchymal stem cells.

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  Figure 2. Role of adipokines in the liver. Adiponectin typically ameliorates hepatic steatosis, suppresses inflammation and attenuates fibrosis, whereas leptin commonly promotes lipid accumulation, pro-inflammatory cytokine production (e.g., TNF-α and IL-6), and fibrogenesis in the setting of obesity and metabolic dysfunction. Both adipokines exhibit context-dependent actions, and their effects may vary with disease stage and microenvironment.

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  Figure 3. Structure and composition of Ad-EVs. EVs are classified into three main types based on biogenesis and size: exosomes (30-150 nm, derived from multivesicular bodies), microvesicles (100-1,000 nm, released from the plasma membrane), and apoptotic bodies (500-2,000 nm, generated during cellular apoptosis). Adipocytes secrete EVs through the formation of MVBs that fuse with the plasma membrane, releasing their contents into the extracellular space. Ad-EVs carry a complex cargo including canonical EV marker proteins (CD9, CD63, CD81, TSG101), lipids, and nucleic acids (such as miRNAs, lncRNAs, and mRNAs). EVs, extracellular vesicles; MVBs, multivesicular bodies; Ad-EVs, adipocyte-derived extracellular vesicles.

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  Figure 4. Role of adipocytes and Ad-EVs in MASLD. Adipocyte hypertrophy in obesity leads to mechanical stress, mitochondrial dysfunction and ER stress, collectively resulting in adipocyte dysfunction. Dysfunctional adipocytes secrete increased amounts of FFAs, adipokines and Ad-EVs. These factors reach the liver and promote hepatic lipid accumulation and inflammatory responses, primarily via activation of the NF-κB pathway in hepatocytes and Kupffer cells, ultimately inducing MASLD. MASLD, metabolic dysfunction-associated steatotic liver disease; ER stress, endoplasmic reticulum stress; Ad-EVs, adipocyte-derived extracellular vesicles; FFA, free fatty acid; TG, triglyceride.

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  Figure 5. Role of adipocytes and Ad-EVs in liver fibrosis and cirrhosis. Activated by adipocyte-derived adipokines (e.g., leptin) and Ad-EVs, hepatic stellate cells (HSCs) transdifferentiate into myofibroblasts, while Kupffer cells become pro-inflammatory. This leads to increased synthesis of collagen types I and III, deposition of extracellular matrix, and progressive liver fibrosis, which may advance to cirrhosis. The TGF-β signaling pathway is a key mediator of HSC activation. Arrows indicate activation and progression. Ad-EVs, adipocyte-derived extracellular vesicles; HSCs, hepatic stellate cells; ER stress, endoplasmic reticulum stress; PDGF, platelet-derived growth factor; CTGF, connective tissue growth factor.

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  Figure 6. Role of adipocytes and Ad-EVs in HCC. In the obese state, adipocyte-secreted adipokines (e.g., leptin) and Ad-EVs promote HCC progression through multiple mechanisms. Adipokines activate oncogenic signaling pathways, such as JAK2/STAT3 and PI3K/AKT/mTOR in liver cancer cells. Ad-EVs carry pathogenic lncRNAs, miRNAs and pro-inflammatory factors that enhance cancer cell proliferation, invasion, and vascular metastasis, and remodel the tumor microenvironment. Ad-EVs, adipocyte-derived extracellular vesicles; HCC, hepatocellular carcinoma; lncRNAs, long non-coding RNAs; miRNAs, microRNAs.

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  Figure 7. Adipocytes and Ad-EVs in the diagnosis and treatment of liver diseases. Adipocyte-secreted adipokines and adipocyte-specific proteins (e.g., A-FABP, ApoF) serve as circulating biomarkers that reflect hepatic inflammation and fibrosis severity, facilitating the non-invasive diagnosis of liver disease. Several adipocyte-specific molecular targets (e.g., GIPR, USP1, ATG7, NPY, INTS6, LIX1L, A2AR, ADM2 and PRDM16) are associated with the progression of liver disease. For therapy, the adiponectin-based agonist JT003 (a dual AdipoR1/R2 agonist) improves insulin resistance in high-fat-diet-induced metabolic dysfunction-associated steatohepatitis (MASH) mice and inhibits HSC activation in CCl4-induced liver fibrosis. Ad-EVs regulate hepatic metabolic pathways, inflammatory responses, and fibrogenesis by transporting specific miRNAs, lncRNAs and proteins. By contrast, therapeutically beneficial vesicles mainly originate from ADSC-EVs, which exert hepatoprotective effects, whereas EVs secreted by mature adipocytes under pathological conditions predominantly play pathogenic roles. Ad-EVs, adipocyte-derived extracellular vesicles; A-FABP, adipocyte fatty acid binding protein; ApoF,…