Human fetal mesenchymal stem cells differentiate into brown and white adipocytes： a role for ERRα in human UCP1 expression

We investigated the ability of fetal mesenchymal stem cells （fMSCs） to differentiate into brown and white adi- pocytes and compared the expression of a number of marker genes and key regulatory factors. We showed that the expression of key adipocyte regulators and markers during differentiation is similar to that in other human and mu- rine adipocyte models, including induction of PPARy2 and FABP4. Notably, we found that the preadipocyte marker, Pref-1, is induced early in differentiation and then declines markedly as the process continues, suggesting that fMSCs first acquire preadipocyte characteristics as they commit to the adipogenic lineage, prior to their differentiation into mature adipocytes. After adipogenic induction, some stem cell isolates differentiated into cells resembling brown adi- pocytes and others into white adipocytes. Detailed investigation of one isolate showed that the novel brown fat-deter- mining factor PRDM16 is expressed both before and after differentiation. Importantly, these cells exhibited elevated basal UCP-1 expression, which was dependent on the activity of the orphan nuclear receptor ERRa, highlighting a novel role for ERRa in human brown fat. Thus fMSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. They also offer invaluable in- sights into the characteristics of human brown fat.

Berberine enhances Ucp1 expression via modulating the NFE2 response element in cold environments: new perspectives on the thermogenesis in brown adipose tissue

Berberine （BBR） has a variety of pharmacological activities. Studies have reported that BBR not only reduces heat stress-induced fever but also inhibits lower body temperatures due to cold stress. Heat stress can be reduced via BBR treatment, which antagonizes HSP70-TNFa to regulate the body temperature alteration. In cold stress, however, the molecular mechanism of BBR-induced inhibition of hypothermia remains unclear. Therefore, we studied whether BBR promoted uncoupling protein 1 （UCP1, a crucial protein of thermogenesis） expression and its mechanism under cold stress. Wild type mice and Ucpl-/- mice were used for the in vivo experiments, and primary brown adipocytes and brown adipocytes HIB-1B were used for the in vitro studies. The cold stress was set at 4℃. The results showed that at 4℃, the body temperature of mice was decreased. BBR effectively inhibited this hypothermia. Simultaneously, Ucpl expression in brown adipose tissue （BAT） cells was significantly increased, and BBR promoted Ucpl expression. However, in Ucpl-knockout mice, the effect of BBR on hypothermia disappeared during cold stress, indicating that the main target for BBR regulation of body temperature was Ucpl. Further studies showed that the transcriptional response element NFE2 （nuclear factor erythroid-derived 2） in the upstream of the Ucpl promoter region contributed to the positive regulatory role on Ucpl expression at lower temperature. BBR could bind to the sequence of NFE2 response element in a temperature-dependent manner. Increased affinity of BBR binding to NFE2 response element in cold stress significantly strengthened and enhanced the expression of Ucpl. This work was important for understanding the role of BBR on thermogenesis in BAT, body temperature regulation and temperature tolerance under cold conditions.