关键词: 小檗碱, Ucp1, 体温, 冷应激, NFE2

Abstract:

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-TNFα 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 protein1 (UCP1, a crucial protein of thermogenesis) expression and its mechanism under cold stress. Wild type mice and Ucp1^–/– mice were used for the in vivo experiments, and primary brown adipocytes and brown adipocytes HIB-1B were used for the in vitrostudies. The cold stress was set at 4 °C. The results showed that at 4 °C, the body temperature of mice was decreased. BBR effectively inhibited this hypothermia. Simultaneously, Ucp1 expression in brown adipose tissue (BAT) cells was significantly increased, and BBR promoted Ucp1 expression. However, in Ucp1-knockout mice, the effect of BBR on hypothermia disappeared during cold stress, indicating that the main target for BBR regulation of body temperature was Ucp1. Further studies showed that the transcriptional response element NFE2 (nuclear factor erythroid-derived 2) in the upstream of theUcp1 promoter region contributedto the positive regulatory role on Ucp1 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 Ucp1. This work was important for understanding the role of BBR on thermogenesis in BAT, body temperature regulation and temperature tolerance under cold conditions.

Key words: Berberine, Ucp1, Thermogenesis, Cold stress, NFE2