Self-Assembled Hyaluronic Acid Nanoparticles Ameliorate Adipose Tissue Inflammation and Insulin Resistance in Diet-Induced Obese Mice

Abstract

Self-assembled hyaluronic acid nanoparticles (HA-NPs), consisting of hydrophobic cores surrounded by a hydrophilic HA shell, have been extensively investigated for biomedical and pharmaceutical applications because of their biocompatibility and receptor-binding properties. Here, we report that an empty HA-NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA-NPs inhibit not only the receptor-mediated internalization of low-molecular-weight (LMW) free HA but also LMW free HA-induced pro-inflammatory gene expression in mouse primary bone marrow-derived macrophages (BMDMs) isolated from wild type mice. Following systemic administration of Cy5.5-labeled HA-NPs, in vivo biodistribution assay and immunofluorescent staining indicate the distribution of HA-NPs and their co-localization with CD44 in adipose tissues including epididymal white adipose tissue (eWAT). However, these effects are largely reduced or rarely observed in BMDMs isolated from CD44-deficient mice. In addition, diet-induced obese (DIO) mice fed a high-fat diet (HFD) show elevated CD44 expression and HA-NP accumulation in eWAT compared to mice on standard diet. Treatment with HA-NPs in HFD-fed DIO mice suppresses macrophage infiltration into adipose tissue and adipose tissue inflammation, leading to improved insulin sensitivity and glycemic control. It is revealed that HA-NP itself can be a therapeutic agent for the treatment of type 2 diabetes. Disclosure J. Rho: None. W. Lee: None. E. Lee: None. C. Kim: None. E. Lee: None. W. Kim: None.