Tetrahydroberberrubine produces anti-obesity effect by activating PGC1α-mediated thermogenesis in white and brown adipose tissue

The increasing incidence of obesity poses great challenges and demands for developing effective therapeutic approaches. We aimed to reveal the anti-obesity effects of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and elucidate its underlying mechanism. The anti-obesity effects of THBru and BBR were assessed and compared using an obese mouse model induced by high fat diet (HFD). THBru was found to markedly ameliorated obesity, indicated by reduced body weight, decreased Lee’s index, lowered epididymal white adipose tissue (WAT) and brown adipose tissue (BAT) fat mass as well as improved dyslipidemia. At the same dose, THBru produced greater anti-obesity effects than BBR. RNA-sequencing and gene set enrichment analysis indicated THBru activated thermogenesis, which was further confirmed in WAT, BAT, and 3T3-L1 cells. Bioinformatics analysis of RNA-sequencing data revealed the candidate gene Pgc1α, a key regulator involved in thermogenesis. Moreover, THBru was demonstrated to elevate the expression of PGC1α by stabilizing its mRNA in WAT, BAT and 3T3-L1 cells. Furthermore, PGC1α knockdown blocked the pro-thermogenic and anti-obesity action of THBru both in vivo and in vitro. This study indicated THBru exerted anti-obesity effects by activating PGC1α-mediated thermogenesis and outlined its potential preventive and therapeutic implications for obesity and related diseases.