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Adipose-derived extracellular vesicles – a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome

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Abstract

Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.

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Abbreviations

ER:

endoplasmic reticulum;

IKKβ:

inhibitory kappaB kinase beta

IL:

interleukins

IRSs:

insulin receptor substrates

JNK:

c-Jun-N-terminal kinase

MCP-1:

monocyte chemoattractant protein 1

MIF:

macrophage inhibitory factor

miR:

microRNA

MMP9:

matrix metalloproteinase 9

PPAR:

peroxisome proliferator-activated receptor

RBP4:

retinol-binding protein 4

TGF-β:

transforming growth factor beta

TIMPs:

tissue inhibitors of matrix metalloproteinases

TNF-α:

tumor necrosis factor alpha.

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Acknowledgements

This work was supported by the Ministry of Science, Technological Development and Innovation of the Republic of Serbia, grant number 200110.

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Authors and Affiliations

  1. Institute of Pathophysiology “Ljubodrag Buba Mihailovic”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Dušan Mladenović & Milena Vesković

  2. Laboratory for Neurophysiology, Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Nikola Šutulović, Dragan Hrnčić & Olivera Stanojlović

  3. Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia

    Lena Radić

  4. University of Belgrade Faculty of Medicine, Department of Endocrinology, UMC Bežanijska kosa, Belgrade, Serbia

    Jelica Bjekić Macut

  5. University of Belgrade Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia

    Djuro Macut

Authors
  1. Dušan Mladenović
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  2. Milena Vesković
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  3. Nikola Šutulović
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  4. Dragan Hrnčić
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  5. Olivera Stanojlović
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  6. Lena Radić
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  7. Jelica Bjekić Macut
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  8. Djuro Macut
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Contributions

All authors contributed to the study conception and design. The idea for this review originated from Djuro Macut. Search of relevant literature related to the role of adipose-derived extracellular vesicles in insulin resistance was performed by Dušan Mladenović and Milena Vesković. Search of relevant literature related to the role of adipose-derived extracellular vesicles in NAFLD was performed by Dušan Mladenović, Milena Vesković, and Nikola Šutulović. Search of relevant literature related to the role of adipose-derived extracellular vesicles in PCOS was performed by Lena Radić, Jelica Bjekić Macut and Dragan Hrnčić. The first draft of the manuscript was written by Dušan Mladenović and all authors commented on previous versions of the manuscript. The final supervision of the manuscript was performed by Olivera Stanojlović and Djuro Macut. Funding was acquired by Olivera Stanojlović. All authors read and approved the final manuscript.

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Correspondence to Dušan Mladenović.

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Mladenović, D., Vesković, M., Šutulović, N. et al. Adipose-derived extracellular vesicles – a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Endocrine (2024). https://doi.org/10.1007/s12020-024-03702-w

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