## 5 Pharmacologic Impact of Exosomes on the Treatment of Metabolic Diseases
Samples were collected from 24 overweight/obese (BMI \(\geq\) 23) subjects and 29 age-matched lean female subjects (BMI! 23) undergoing elective abdominal surgery for benign, noninfective gynecological conditions. Overweight and obese individuals had poorer glucose and lipid profiles and greater insulin resistance. miR-34a expression was significantly higher in both adipose tissue types compared to lean individuals, with a more pronounced increase in visceral fat than in subcutaneous fat (\(p\)! 0.05) [86; 102] (Figure 3). In a report, treating nonobese C57B6J mice with plasma-isolated exosomes from obese mice fed a high-fat diet for 15 weeks leads to glucose intolerance. Key microRNAs associated with this effect include miR-122, miR-192, miR-27a-3p, and miR-27b-3p. Additionally, exosomes from obese mice have been shown to cause insulin resistance when used to treat nonobese mice. It has been shown that the miRNA composition of exosomes is strongly related to a high body fat index [87; 103] (Figure 3). This body of evidence points to exosomes as vehicles for miRNAs with profound effects on metabolism, which in turn indicates a great potential for novel therapeutic strategies to modulate the miRNA content of exosomes. Figure 3: Exosomal microRNA (miRNA) released by metabolic tissues impact insulin signaling, inflammation, vascular function, adipocyte biology, and \(\beta\)-cell physiology, which are connected to systemic metabolism and mechanisms of chronic diseases [92; 101]. **(A)** Exosomal miRNAs derived from adipocytes are associated with mechanisms of macrophage polarization to M1, lipogenesis, and adipocyte hypertrophy, releasing miR-16, miR-27a, miR-146b, miR-122, miR-155, and miR-29a. Exosomes from adipose tissue macrophages (ATMs) contribute to the regulation of insulin sensitivity by miR-155 and miR-29a; conversely, exosomes secreted by M2 ATMs containing miR-690 increase whole-body insulin sensitivity [92; 101]. **(B)** Insulin resistance in skeletal muscle releases miR-16 in exosomes, stimulating \(\beta\) cell proliferation to boost insulin production and prevent hyperglycemia. Skeletal muscle enhances crucial processes, such as cell cycle regulation and cell adhesion [92; 101]. (**C**) Inflammatory signals prompt endothelial cells (ECs) to release exosomes rich in miR-383-3p and let-7d-3p. ECs also secrete cav1-containing exosomes that interact with adipocytes, which release their exosomes taken up by ECs, inducing a crucial bidirectional communication network [83; 98]. (**D**) Exosomes secreted from beta cells of healthy patients reduce the formation of amyloid plaques by hIAPP through a direct binding mechanism. This is contrary to what occurs in exosomes from patients with DM2, where the formation of these plaques is increased [58; 66]. (**E**) Lipotoxic hepatocytes release exosomes that activate hepatic stellate cells, driving the fibrotic changes seen in non-alcoholic steatohepatitis (NASH) [91; 104]. Evidence suggests that damaged liver cells release exosomes with Toll-3 receptors that bind to healthy hepatocytes and induce proinflammatory factors for their repair and fibrosis [41; 53] Adapted from Figure 4 of Roi Isaac et al., 2021 [101].