Diabetes mellitus (DM), one of the most prevalent illnesses in the world, has an impact on every organ in the body (ANON, 2021). Being a metabolic disease, diabetes mellitus (DM) is typified by hyperglycemia brought on by insulin resistance (IR) and/or insufficient insulin production. Type 2 DM (T2DM) covers more than 90 % of diabetics. Numerous factors have been found to impact the incidence of T2DM, including the environment, genetic risk factors, and lifestyle choices like smoking, drinking alcohol, consuming high-fat foods and beverages, and being obese (Ma et al., 2023, Bi et al., 2012). In recent years, research on the pathogenesis of T2DM has shifted from integrating all potential systemic pathogenic factors to focusing on specific localized lesions, such as adipose tissue inflammation.
Adipose tissue is a multifunctional organ found in multiple sections of the human body. It helps the body maintain an energy balance. Obesity, a non-physiological development of adipose tissue, has the potential to disrupt this energy homeostasis, which can result in the development of several illnesses, including T2DM, dyslipidemia, cardiovascular disease, fatty liver disease, hypertension and others (Zwick et al., 2018, Barthelemy et al., 2023). One characteristic of obesity is adipose tissue with chronic low-grade inflammation, which is essential for the emergence of insulin resistance and T2DM (Zatterale et al., 2019). Macrophage infiltration and the heightened activation of pro-inflammatory phenotypes in adipose tissue are indicators of chronic low-grade inflammation. In contrast, in lean individuals, the anti-inflammatory phenotype is more pronounced (Ren et al., 2022, Harford et al., 2011). Accordingly, adipose tissue macrophages (ATMs) have been reported to impair insulin sensitivity and encourage persistent low-grade inflammation linked to obesity through secreting high levels of pro-inflammatory cytokines (Li et al., 2023, Xu et al., 2022). Nevertheless, the molecular pathways and their pathogenic roles in T2DM remain incompletely understood.
Exosomes are membrane-bound, 40–160 nm vesicles released by parent cells that are able to alter intercellular communication by delivering various bioactive cargos to the target cells, including lipids, proteins, and nucleic acids (Kalluri and LeBleu, 2020). MicroRNAs (miRNAs) are approximately 19–25 nucleotides long, also known as single-stranded, short non-coding RNAs. MiRNAs are normally encapsulated in exosomes and contribute to cellular interaction by post-transcriptionally inhibiting the expression of target genes, mostly via promoting mRNA degradation and/or inhibiting protein translation (Cech and Steitz, 2014, Garcia-Martin et al., 2022). Recent research has explored the role of exosomal miRNAs that can modulate inflammation through immune cell interaction and pathway regulation. For example, mesenchymal stem cell-derived exosomal miRNAs have shown promise in reducing inflammation by targeting inflammatory pathways, such as the NF-κB and NLRP3 signaling pathways. Exosomal miRNAs like miR-26a-5p target TLR4 to prevent inflammatory responses in conditions like diabetic nephropathy (Nail et al., 2023). Meanwhile, emerging evidence suggests that ATMs secrete exosomes that include miRNA payload to control insulin resistance. For instance, prior investigations have revealed that obese mice ATM-derived exosomal miR-155 reduces their sensitivity to insulin via targeting PPAR-γ signaling in vivo and in vitro (Ying et al., 2017). Evidence also suggests that ATM-derived exosomal miR-210–5p promoted insulin resistance in small for gestational age with catch-up growth rats by targeting SID1 transmembrane family member 2 (Xiong et al., 2023). Furthermore, in vivo and in vitro exosomal miR-29a produced from ATMs in obese mice may affect the insulin sensitivity of lean mice by PPAR-γ signaling (Liu et al., 2019). While the role of exosomal miRNAs has been studied in various diseases, their pathogenic roles in T2DM, particularly in adipose tissue inflammation, remain underexplored. However, the specific pathogenic roles of ATM-derived exosomal miRNAs in adipose tissue inflammation have not been previously explored in T2DM.
In this instance, we extracted and examined exosomes from the macrophages of healthy individuals or diabetic patients’ visceral adipose tissues (VATs). We discovered miR-500a-5p is elevated in ATM-derived exosomes of patients with diabetes, which can be transferred into adipocytes and promote adipocytes inflammation by activating NLRP3 inflammasome. Subsequently, we found that Nrf2 contains binding sequences for miR-500a-5p. Studies have demonstrated its pivotal role in mitigating insulin resistance and regulating inflammation signaling (Shrestha et al., 2024, Włodarski et al., 2020). We reveal that Nrf2 mediates the effects of miR-500a-5p on inducing inflammation in adipocytes and is most likely the direct target of miR-500a-5p.
