Targeting adipose remodeling: Synergistic mechanisms of drugs and adipose-derived stem cells in obese type 2 diabetes mellitus

Figure 3 Stem cell secretome. Integrated adipose-derived stem cell secretome suppresses inflammatory signaling and restores insulin action in adipose tissue with interleukin-10, transforming growth factor-β activate signal transducer and activator of transcription 3, and mothers against decapentaplegic homolog 2/3, which repress the toll-like receptor-IκB kinase β/c-Jun N-terminal kinase-nuclear factor kappa B axis, lowering serine-phosphorylated insulin receptor substrate-1 and re-establishing phosphoinositide 3-kinase-protein kinase B-glucose transporter 4-dependent glucose uptake in adipocytes. Adipose-derived stem cell-derived extracellular vesicles deliver miR-223-3p and miR-146a to inhibit NOD-like receptor family pyrin domain containing 3 and transforming growth factor-β-activated kinase 1/tumor necrosis factor receptor-associated factor 6 signaling, further dampening innate immune activation. By contrast, obesogenic miR-155 and miR-29a (dashed) promote M1 polarization and exacerbate insulin resistance. The net effect is a shift of the adipose immune milieu toward resolution with improved insulin signaling and glucose uptake. Solid arrows indicate activation; dashed lines denote context-dependent or deleterious routes. IL-10: Interleukin-10; TGF-β: Transforming growth factor-β; STAT3: Signal transducer and activator of transcription 3; SMAD2/3: Mothers against decapentaplegic homolog 2/3; TLR: Toll-like receptor; IKKβ: IκB kinase β; JNK: C-Jun N-terminal kinase; NF-κB: Nuclear factor kappa B; IRS-1: Insulin receptor substrate-1; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; GLUT4: Glucose transporter 4; ADSCs: Adipose-derived stem cells; EVs: Extracellular vesicles; NLRP3: NOD-like receptor family pyrin domain containing 3; TAK1: Transforming growth factor-β-activated kinase 1; TRAF6: Tumor necrosis factor receptor-associated factor 6; miR: MicroRNA.