Total saponins from Panax japonicus alleviate insulin resistance via exosomal miR204/Elovl6-mediated adipocyte-macrophage crosstalk.

Insulin resistance (IR) is a key factor in the development of type 2 diabetes, and M2-like macrophages are important in maintaining normal glucose homeostasis. Our previous research has demonstrated that the total saponins from Panax japonicus (TSPJ) reduce IR in adipocytes and promote the M2 polarization of macrophages, but the molecular mechanism is unclear. In the study, we aimed to elucidate whether TSPJ mitigate IR by enhancing the intercellular communication between adipocytes and macrophages and describe how the exosomes from bone marrow-derived macrophages (BMDMs) modulate the insulin sensitivity of adipocytes via miR204. We used both in vitro and in vivo models to study the effects of TSPJ on IR, with a particular emphasis on the exosomes from M2-type BMDMs. Furthermore, we investigated the mechanisms by which exosomal miR204 and its downstream target Elovl6 influence IR in an obese mouse model, as well as in adipocytes with double inhibition of miR204 and Elovl6. In the animal model, TSPJ significantly increased miR204 expression in BMDMs-derived exosomes and decreased the level of Elovl6 in adipocytes. However, when the C75BL/6 mice had miR204 ablation, TSPJ became less capable of enhancing insulin sensitivity, and the expressions of Irs1, Insr, and Slc2a4 in the adipose tissue decreased. In the cell model where the macrophages carried miR204 ablation and the adipocytes had Elovl6 knockdown, the expressions of IR-related genes increased in the adipocytes. TSPJ mitigated IR through adipocyte-BMDM crosstalk mediated by exosomes via the miR204/Elovl6 pathway.