Nanomedicine targeting PPAR in adipose tissue macrophages improves lipid metabolism and obesity-induced metabolic dysfunction

Excess body fat leads to an overabundance of adipose tissue macrophages (AT MOs) with altered phenotypes that play pathogenic roles in obesity comorbidities including diabetes and cancer. Peroxisome proliferator-activated receptors (PPARs) are leading targets to modulate AT ΜΦ phenotype. Here, we developed a dextran-based nanomedicine that delivers PPARa/γ agonists to AT MOs and improves obesity and diabetic phenotypes in vivo. Within 1 week of treatment, AT MOs decreased and became lipid laden, while extracellular vesicles secreted from AT decreased and reduced in lipid content. Within 2 weeks, glucose tolerance returned to levels of lean controls, followed by weight loss and reduced food intake. After 4 weeks, AT browning and amelioration of hepatic steatosis were evident. The physiological shifts were reproducible in three rodent models of obesity, spanning sexes and gonadal status. Effects were enhanced for the targeted nanomedicine compared with free drugs at equivalent doses, supporting the hypothesis that targeted PPAR activation in AT MOs benefits systemic metabolism.