Browning white adipose tissue using adipose stromal cell-targeted resveratrol-loaded nanoparticles for combating obesity

Authors: ZU, YUJIAO - Texas Tech University; ZHAO, LING - University Of Tennessee; HAO, LEI - Texas Tech University; MACHREF, YEHAI - Texas Tech University; ZABET-MOGHADDAM, MASOUD - Texas Tech University; KEYEL, PETER - Texas Tech University; ABBASI, MEHRNAZ - Texas Tech University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DAWSON, JOHN - Texas Tech University; ZHANG, RUIWEN - University Of Houston; NIE, SHUFANG - Texas Tech University; MOUSTAID-MOUSSA, NAIMA - Texas Tech University; KOLONIN, MIKHAIL - University Of Texas; DAQUINAG, ALEXES - University Of Texas; BRANDI, LUIS - Texas Tech University; WARRAICH, IFRAN - Texas Tech University; SAN FRANCISCO, SUSAN - Texas Tech University; SUN, XIAOCUN - University Of Tennessee; FAN, ZHAOYANG - Texas Tech University; WANG, SHU - Texas Tech University

Submitted to: Journal of Controlled Release
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2021
Publication Date: 3/23/2021
Citation: Zu, Y., Zhao, L., Hao, L., Machref, Y., Zabet-Moghaddam, M., Keyel, P.A., Abbasi, M., Wu, D., Dawson, J.A., Zhang, R., Nie, S., Moustaid-Moussa, N., Kolonin, M.G., Daquinag, A.C., Brandi, L., Warraich, I., San Francisco, S.K., Sun, X., Fan, Z., Wang, S. 2021. Browning white adipose tissue using adipose stromal cell-targeted resveratrol-loaded nanoparticles for combating obesity. Journal of Controlled Release. 333:339-351. https://doi.org/10.1016/j.jconrel.2021.03.022.
DOI: https://doi.org/10.1016/j.jconrel.2021.03.022

Interpretive Summary: Brown and white adipose tissue (WAT) are two types of human fat cells. Brown adipose tissue causes the body to burn more energy through heat production directly influencing energy balance within the body. Consequently, the browning of white adipose tissue is a potential strategy to manage bodyweight and obesity related chronic diseases. However, new research has been limited by the negative side-effects and toxicities of the currently available methods that promote the browning of WAT. In order to eliminate these barriers, we propose a new method; the targeted delivery of browning agents to adipose stromal cells (ASCs). These browning agents cause ASCs, which are found in WAT located underneath the skin, to convert into beige adipose tissue. In this study, the ASC-targeted delivery of an agent administered intravenously to obese mice resulted in a corresponding decrease in fat mass accompanied by improved glucose levels and decreased inflammation. These findings suggest ASC-targeted delivery of browning agents could be transformative technology in effectively reducing obesity and obesity related chronic diseases without toxicity.

Technical Abstract: Enhancing thermogenic energy expenditure via promoting the browning of white adipose tissue (WAT) is a potential therapeutic strategy to manage energy imbalance and the consequent comorbidities associated with excess body weight. Adverse effects and toxicities of currently available methods to induce browning of WAT have retarded exploration of this promising therapeutic approach. Targeted delivery of browning agents to adipose stromal cells (ASCs) in subcutaneous WAT to induce differentiation into beige adipocytes may overcome these barriers. Herein, we report for the first time, ASC-targeted delivery of trans-resveratrol (R), a representative agent, using ligand-coated R-encapsulated nanoparticles (L-Rnano) that selectively bind to glycanation site-deficient decorin receptors on ASCs. After biweekly intravenous administration of L-Rnano to obese C57BL/6 J mice for 5 weeks targeted R delivery significantly induced ASCs differentiation into beige adipocytes, which subsequently resulted in 40% decrease in fat mass, accompanied by improved glucose homeostasis and decreased inflammation. Our results suggest that the ASC-targeted nanoparticle delivery of browning agents could be a transformative technology in combating obesity and its comorbidities with high efficacy and low toxicity.