Development of drug delivery system that modulates adipose tissue function.

PROJECT SUMMARY/ABSTRACT Obesity, affecting over 40% of U.S. adults, is a major health concern that contributes to the development of metabolic disorders such as type 2 diabetes and insulin resistance. Current FDA-approved hunger suppressant drugs can induce weight loss but do not directly impact adipose tissue, leading to quick weight regain once treatment is stopped. White adipose tissue (WAT), which stores excess fat, plays a central role in obesity, while brown adipose tissue (BAT) helps burn fat through fat oxidation, converting fatty acids into energy and increasing thermogenesis. This project aims to create a drug delivery system that is retained in the adipose tissue and promotes fat browning—the conversion of WAT to a more metabolically active state similar to BAT—to enhance systemic metabolism. The overarching goal is to develop a locally injected adipose tissue nano-reservoir for continuous delivery of forskolin, a cyclic AMP activator molecule known to stimulate fat thermogenesis in adipose tissue. The project comprises three specific aims: Aim 1 focuses on establishing a correlation between the physicochemical properties of engineered hybrid lipid-coated mesoporous silica nanoparticles (LCMSN) and the cell uptake in the adipose tissue as well as the in vivo distribution of LCMSN and forskolin, assessing how shell configurations impact cell retention, forskolin release and efficacy. Aim 2 aims to identify the optimal properties and dosing strategies for the LCMSN to effectively induce thermogenesis in WAT, evaluating its impact on systemic metabolism, energy expenditure, and weight management in mice on a high-sucrose high-fat diet. Aim 3 will determine the efficacy of this nanomedicine in promoting weight loss in a diet-induced obesity model, correlating treatment outcomes with changes in food intake, body composition, and metabolic markers. Through preclinical studies, this project seeks to assess the impact of optimized forskolin delivery on weight management and metabolic health, ultimately creating a novel targeted tool for long-term obesity management and improved patient care.