Adipose stem cell-targeted local delivery of forskolin induces de novo beige adipogenesis and adipose tissue browning to combat obesity.

Abstract

Inducing white adipose tissue (WAT) browning is a promising strategy to combat obesity and metabolic disorders. However, current browning inducers often suffer from off-target effects and poor durability. Beige adipocytes, which can arise through de novo differentiation from adipose-derived stromal/stem cells (ASCs), offer a potential avenue for sustained thermogenesis. Here, we identified that forskolin (FSK) effectively induced the differentiation of C3H10T1/2 cells (a mesenchymal stem cell line) into beige adipocytes, evidenced by multilocular lipid droplets, enhanced mitochondrial biogenesis and function, and elevated uncoupling protein 1 expression. To overcome its poor bioavailability and lack of targeting specificity, we developed ASCs-targeting-peptide (ASP, sequence: GSWKYWFGEGGC) modified FSK nanoparticles (ASP@FSK NPs) by encapsulating FSK in the hybrid FDA-approved biodegradable polymers poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG)-ylated PLGA. ASP@FSK NPs selectively bind to glycanation site-deficient decorin (ΔDCN) receptors on ASCs, enabling prolonged retention and localized delivery within inguinal WAT (iWAT). In a high-fat diet-induced obesity model, local administration of ASP@FSK NPs significantly reduced body weight (∼30%), promoted de novo browning of iWAT, and alleviated liver steatosis in high-fat diet-induced obese mice, while expanding the therapeutic window of FSK and without apparent toxicity. Collectively, this study demonstrated that FSK could be developed as a potent inducer of de novo beige adipogenesis and targeted delivery of FSK to ASCs might provide a valuable strategy for the treatment of obesity. STATEMENT OF SIGNIFICANCE: Obesity and metabolic syndromes remain global health challenges, and strategies that induce white adipose tissue browning hold great therapeutic potential. However, existing browning agents are limited by systemic toxicity, off-target effects, and poor sustainability. This study addresses these critical gaps by demonstrating that forskolin (FSK) drives de novo beige adipocyte differentiation from mesenchymal stem cells. We further developed an adipose-derived stem cell-targeted nanoparticle system (ASP@FSK NPs) for localized and sustained delivery. In obese mice, ASP@FSK NPs efficiently promoted inguinal WAT browning, alleviated adiposity and hepatic steatosis, and expanded the therapeutic window of FSK without obvious toxicity. This work establishes a targeted and durable approach for WAT browning and obesity treatment by integrating a progenitor-directed biological strategy with precision nanomedicine.