Global epidemics of obesity and its associated comorbidities pose formidable challenges to human health. Current few medications available for obesity treatment only produce modest effects and are usually accompanied with unpleasant, potentially harmful side effects. There is accumulating evidence that significant metabolic differences that distinguish beige/brown adipocytes from white adipocytes can potentially be exploited to establish new therapeutic strategies for treatment and prevention of obesity. It has been recently demonstrated that inhibition of Notch signaling through intraperitoneal injection of dibenzazepine (DBZ), a ?- secretase inhibitor, results in profound transformation of white adipocytes into beige adipocytes (browning) and consequently reduces obesity and improves glucose balance in obese mice. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Thus, there is a critical need for the development of new drug delivery systems that will allow selective spatio-temporal delivery of Notch inhibitor DBZ to adipose tissues. The goal of this proposal is to develop a biodegradable polymeric nanoparticulate system designed to deliver DBZ in a controlled manner to white adipose tissues (WAT) to achieve browning of white adipocytes and thereby reduce obesity in obese mice. The collaborative research work by Dr. Meng Deng and Dr. Shihuan Kuang has recently demonstrated the promise of DBZ-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (DBZ-NPs) for direct intracellular delivery of DBZ to the adipocytes within specific subcutaneous WAT depots. This has resulted in the formation of Adipo Therapeutics to explore commercial opportunities linked to these findings. PLGA has been selected as the delivery system because it is an FDA-approved biodegradable and biocompatible material. The goal of this project will be achieved by performing the following: Aim 1: Optimize a DBZ-NP system for intracellular delivery of DBZ to promote browning of white adipocytes. Aim 2: Establish the efficacy of the optimized DBZ-NPs to reduce obesity in mice. The overall hypothesis is that DBZ-NPs can be optimized to provide sustained intracellular release of biologically-active DBZ both in culture and in vivo, and will suppress Notch signaling, thereby inducing browning of white adipocytes and reducing obesity in a mouse model. At the end of Phase I, Adipo Therapeutics expects to have optimized a novel technology platform composed of polymer-based nanoparticles to induce beige adipocyte biogenesis. During Phase II, Adipo Therapeutics plans to explore clinical translation of the polymer-based technology platform. It is also expected that application of this engineered nanoparticulate system will improve fundamental understanding of the role of Notch signaling in browning and regulating body energy homeostasis. Successful completion of the project will have an impact in development of safe and effective therapeutic strategies for the treatment for obesity.
Public Health Relevance Statement: Transformation of white adipocytes into beige adipocytes (browning) has great potential for development of new therapeutics for treatment and prevention of obesity. Current strategies for enhancement of beige adipocyte biogenesis and function involve genetic and systemic pharmacological manipulations, which are associated with significant translational challenges due to off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. The proposed study seeks to develop a clinically translatable polymeric nanoparticulate system that induces browning of white adipocytes to reduce obesity in a spatio-temporally controlled manner.
Project Terms: 20 year old; absorption; Adipocytes; Adipose tissue; Adult; Adverse effects; adverse outcome; Atherosclerosis; base; Biocompatible Materials; biodegradable polymer; Biogenesis; Biological; Brown Fat; Cells; Chronic Disease; clinical practice; clinical translation; clinically translatable; Collaborations; Comorbidity; controlled release; cost; design; Desire for food; Development; Digestion; Disease; Drug Delivery Systems; drug distribution; effective therapy; Energy Intake; Energy Metabolism; Engineering; Epidemic; Equilibrium; Fatty Liver; FDA approved; gamma secretase; Gastrointestinal tract structure; Genetic; Glucose; Glycolic-Lactic Acid Polyester; Goals; GTP-Binding Protein alpha Subunits, Gs; Health; High Fat Diet; Homeostasis; Hormonal; Human; improved; In Vitro; in vivo; inhibitor/antagonist; Injections; innovative technologies; Intraperitoneal Injections; Link; Lipids; Liver diseases; Location; Medicare; Metabolic; mouse model; Mus; nanoparticle; nanoparticle drug; nanoparticulate; Neuraxis; Neurons; new technology; new therapeutic target; Non-Insulin-Dependent Diabetes Mellitus; notch protein; novel therapeutic intervention; novel therapeutics; Nutrient; Obese Mice; Obesity; obesity prevention; obesity treatment; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase; Polymers; Property; Public Health; Research; Risk; Role; Safety; Signal Transduction; Small Business Innovation Research Grant; spatiotemporal; subcutaneous; System; Technology; Therapeutic; Tissues; Translations; Treatment Efficacy; treatment strategy; Universities; Work
