Direct and Indirect Effects of Guggulsterone on the Induction of Beiging in Mature 3T3-L1 Adipocytes
Phytochemicals have long demonstrated anti-obesity properties in adipocytes. Their ability, however, to induce browning in white adipose tissue is only beginning to emerge. We have recently established thatthe white adipocyte cell line, 3T3-L1, is capable of beiging under beta-adrenergic conditions. Herein, we investigated whether the plant steroid guggulsterone (GS), studied for its antiobesity and antilipidemiceffects, can induce beiging in 3T3-L1s. 3T3-L1 preadipocytes were differentiated using established protocols supplemented with rosiglitazone and thyroid hormone. Direct effects of GS were measured by treating mature 3T3-L1 cells for 24 hours. Indirect effects were measured by treating mature 3T3-L1 cells with conditioned media from GS-treated RAW 264.7 cells, a murine macrophage cell line. Directtreatment of 3T3-L1s with GS resulted in increased lipolysis, increased mitochondrial activity (11%), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) levels by 250%. 3T3-L1s also demonstrated an increase in the expression of uncoupling protein 1 (UCP1) by 200% and beige marker, Tbox protein 1 (TBX1) by 80%compared to untreated control cells. Furthermore, this was accompanied by increased levels of G protein-coupled bile acid receptor (TGR5) and its downstream target iodothyronine deiodinase 2 (DIO2). Treatment of RAW 264.7 cells with GS induced a 60% increase incatecholamine release into the media. 3T3-L1 adipocytes increased the expression of DIO2 and UCP1 following 24 hours of incubation with conditioned media obtained from macrophages. Results from this study demonstrate that GS can potentially induce beiging in white adipose tissue through two distinct mechanisms: (1) direct signaling through the TGR5-cAMP-DIO2 pathway and (2) indirectly through stimulating catecholamine release from macrophages. Thus, our studies demonstrate that GS may improve the metabolic capacity of adipose tissue thereby counteracting the effects of obesity.
Miller, C. N.; Azhar, Y.; Parmar, A.; Samuels, J.; Shashidharamurthy, Rangaiah; and Rayalam, Srujana, "Direct and Indirect Effects of Guggulsterone on the Induction of Beiging in Mature 3T3-L1 Adipocytes" (2017). PCOM Scholarly Papers. 1880.