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Indomethacin, a nonsteroidal anti‐inflammatory drug, enhanced brown fat activity in vitro and in vivo

Obesity is a major public health problem. Activating brown adipose tissue (BAT) can increase energy expenditure through thermogenesis. BAT has been considered as an innovative therapeutic target for combating obesity and its comorbidities. Indomethacin, a nonsteroidal anti‐inflammatory drug (NSAID), has the capacity to induce white adipocyte differentiation. But its effects on pre‐brown adipocytes differentiation, on animal BAT activation, and obesity are unknown. The objectives of this project are to determine indomethacin's activities in regulating brown adipocyte differentiation in vitro, and to investigate its anti‐obesity activities and underlying mechanisms in male C57BL/6 mice. The murine brown fat cells were treated with indomethacin (2, 5, 10, 20, 50 μM) or the vehicle control DMSO for 5 days. Oil‐Red‐O staining showed that indomethacin enhanced pre‐brown adipocytes differentiation into adipocytes compared to the vehicle control. Data from real‐time PCR and Western blot analysis demonstrated that indomethacin increased both mRNA and protein expression of brown specific marker genes, such as UCP‐1 and PGC1α, in a dose‐dependent manner. Mechanistically, we found that indomethacin significant activated PPARγ. Male C57BL/6 mice became obese after feeding them with a high fat diet for 9 weeks. Implantation of ALZET osmotic mini‐pumps allowed targeted delivery of vehicle or indomethacin (36 μg/day) to BAT for additional 4 weeks while they were maintained on the high fat diet. Indomethacin treatment did not change food intake, body weight, and total fat mass, while there was a trend towards less epididymal white adipose tissue mass in indomethacin‐treated as compared to vehicle‐treated mice. In addition, indomethacin significantly decreased BAT mass, fasting blood glucose levels and plasma TG levels. H&E staining showed that brown adipocytes of indomethacin‐treated mice contained numerous smaller droplets compared with that of control mice, suggesting that BAT in indomethacin‐treated mice was more active than them in control mice. Moreover, indomethacin significantly increased UCP1 and PGC‐1α mRNA expression in BAT. We conclude that indomethacin increases brown fat activity in pre‐brown adipocytes and mice, suggesting that indomethacin may also be used to treat obesity and its related complications.