(626g) Treating Obesity and Glucose Intolerance through Polymer Scaffold Delivery of Resveratrol to the Adipose Tissue

Resveratrol, a natural polyphenol found in the skin of red grapes, has become a popular therapeutic compound in studies of obesity and type 2 diabetes after it was demonstrated to mimic the effects of caloric restriction in various animal models, resulting in decreases in fat accumulation and improved glucose tolerance. However, upon translation into the clinical setting, oral or intravenous administration of resveratrol produced underwhelming results, which was attributed in part to the compound’s poor bioavailability and a lack of patient compliance. To address these issues, we encapsulated resveratrol within biodegradable polymeric scaffolds for implant into the adipose tissue, an integral tissue in the pathogenesis of obesity and type 2 diabetes. We fabricated scaffolds by first encapsulating resveratrol within poly(lactide-co-glycolide) (PLG) microparticles using a single emulsion technique. We then mixed the particles with sodium chloride, a sacrificial porogen, and pelleted the mixture in a die. The pellet was then gas foamed in CO₂ and the sodium chloride was removed by washing in water, leaving behind a porous polymer matrix containing resveratrol. Quantification of resveratrol content within the scaffolds revealed a loading of 45 mg of resveratrol per mg of polymer, with scaffolds weighing 2 mg. The therapeutic efficacy of resveratrol scaffolds was tested by implant into the epididymal adipose tissue of mice receiving a 60% fat diet, which results in significant weight gain and glucose intolerance. Interestingly, resveratrol scaffold implant significantly reduced fat gain and improved glucose intolerance caused by a 60% fat diet as measured by dual-energy x-ray absorptiometry and an intraperitoneal glucose tolerance test (IPGTT), respectively. The reduction in weight gain was attributed to elevations in fatty acid oxidation at the implant site through elevations in carnitine palmitoyltransferase I (CPT1), the rate limiting enzyme in fatty acid oxidation, while improvements in glucose tolerance correlated with improved insulin signaling in the adipose tissue. Importantly, oral administration of resveratrol requires daily doses of 20 to 400 mg/kg to protect rodents and primates from high fat diet induced obesity and diabetes; however, we achieved comparable results with a single dose of 20 mg/kg. a small fraction of the doses used in these studies. Collectively, we expect this work highlight the power of biomaterial drug delivery to the adipose tissue as a platform for treating obesity and type 2 diabetes and to aid in the development of new treatments for diabetes, the most common metabolic disorder in the United States.