Resveratrol-Loaded Liposomes: Browning Subcutaneous White Adipose Tissue for Combating Obesity in C57BL/6 J Mice

Abstract

Abstract Objectives Trans-resveratrol (R) is a potential browning compound and can induce beige adipocyte formation in subcutaneous white adipose tissue (WAT). However, R's low aqueous solubility and high hepatic metabolism limit its application in combating obesity. Hence, we synthesized R-loaded liposomes (Rlipo). The objectives of this study are to measure Rlipo characteristics and determine the browning and anti-obesity efficacy for local delivery of Rlipo to inguinal WAT (I-WAT) in obese mice. Methods The particle size and zeta potential of Rlipo and void liposomes (Vlipo) were measured using a Brookhaven BI-MAS particle size and ZetaPALS analyzer, respectively. Their physical stability was measured daily at 4, 22 and 37°C for 7 days. The in vitro R release pattern of Rlipo was measured using a dialysis method. For determining anti-obesity activities, C57BL/6 J mice were fed the high-fat diet (HFD) for 9 weeks. During week 5–9, mice were treated with saline, free R, Vlipo, or Rlipo via I-WAT injection twice per week. Food intake, body weight, and body composition were measured weekly, and the glucose tolerance test was conducted at week 9. After sacrifice, we collected and measured the mass of liver and fat depots. The mRNA levels of uncoupling protein-1 (UCP-1) and other beige markers in I-WAT were measured using real-time PCR. Results As compared to free R, Rlipo increased R's aqueous solubility by more than 30 times. The particle sizes of Rlipo and Vlipo were about 100 nm. Their zeta potentials were around −25 mV. Both Rlipo and Vlipo have good physical stability at 3 tested temperatures for 7 days and Rlipo exhibited a prolonged-release manner. In the animal study, Rlipo-treated compared to free R-treated mice had 1.2-, 1.4-, 1.6-, 1.5-fold lower body weight, fat %, I-WAT, and gonadal WAT mass, respectively, which were correlated with 1.8- and 2.6-fold higher UCP-1 and TMEM26 mRNA levels in I-WAT. However, no significant differences were found in food intake and the glucose tolerance test. Conclusions Rlipo increased R's aqueous solubility and improved its sustained release manner. Rlipo had higher anti-obesity activities than free R, which were correlated with increased expression of beige markers in I-WAT of mice. Browning subcutaneous WAT using Rlipo might provide an innovative and efficient approach for combating obesity. Funding Sources NIH 1R15AT010395.