Date of Award
Doctor of Philosophy
Jay Whelan, Guoxun Chen, Ahmed Bettaieb, Madhu Dhar
Obesity is a global pandemic and its comorbidities are the top causes of preventable death in America. Brown and inducible beige fat can significantly contribute to energy expenditure, possibly leading to weight loss, and is considered a novel approach to combat obesity. Browning of white adipocytes can be achieved using cold exposure, β [beta]-adrenergic receptor (β-AR) and peroxisome proliferator-activated receptor gamma (PPAR [gamma]) agonists, and some nutritional and pharmaceutical agents. Trans-resveratrol (Res) and indomethacin (Indo) have shown promising abilities to promote browning. Res has been shown to induce browning in vitro and in vivo; however, its rapid metabolism and poor aqueous solubility reduce bioavailability, limiting its clinical utility. Therefore, two forms of nanocarriers were synthesized to encapsulate Res (RNano and RLipo), both of which led to enhanced aqueous solubility, chemical stability, and sustained release patterns (Chapter III). Both RNano and RLipo significantly enhanced browning of murine 3T3-L1 adipocytes as shown by increased uncoupling protein 1 (Ucp1) and PPAR coactivator-1 alpha (Pgc1 [alpha]) mRNA expression when stimulated by β-AR-agonist, isoproterenol. To further enhance Res effectiveness, a ligand for delta-decorin ( [delta]DCN), a receptor specific to adipose stromal cells (ASCs) within white adipose tissue (WAT), was incorporated into nanocarriers (L-NR) (Chapter IV). Freshly isolated ASCs from the inguinal WAT of C57Bl/6J mice were used to confirm DCN protein expression, enhanced uptake of the ligand-bound nanocarrier, and augmented browning using two different differentiation models. Finally, the browning and brown adipogenic capacity of the non-steroidal anti-inflammatory drug, Indo, was tested using murine 3T3-L1, human primary subcutaneous (HPsubQ), and human brown (HBr) adipocytes. Indo is shown to have strong partial-PPAR-agonist activities (Chapter V). It was found that Indo dose-dependently promoted browning in 3T3-L1 and HPsubQ adipocytes as well as enhanced brown adipogenesis in HBr adipocytes via its PPAR-agonist activity as demonstrated by increased UCP1 expression, mitochondrial biogenesis, proton leak, and respiratory capacity.In conclusion, we have shown enhanced browning capacity of Res using nanocarriers, which is augmented by the addition of ASC-targeting peptides as well as browning and brown adipogenesis induced by Indo. Given these results, these compounds can be considered novel browning agents to help combat obesity.
Overby, Haley Beth, "Exploring Novel Anti-Obesity Strategies: Nutritional and Pharmacological Interventions to Induce Browning and Brown Adipogenesis. " PhD diss., University of Tennessee, 2019.