State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, China; State Key Laboratory -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, China.
Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow, Russian Federation.
Biochem Pharmacol. 2024 Aug;226:116381. doi: 10.1016/j.bcp.2024.116381. Epub 2024 Jun 21.
The escalating prevalence of obesity presents formidable challenges, necessitating the development of effective therapeutic strategies. In this study, we aimed to elucidate the preventive effects on obesity of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and to unravel its underlying mechanism. Using an obese mouse model induced by a high-fat diet (HFD), THBru was found to markedly ameliorate obesity, as evidenced by reduced body weight, decreased Lee's index, diminished fat mass in epididymal white adipose tissue (WAT) and brown adipose tissue (BAT), alongside improved dyslipidemia. Notably, at the same dose, THBru exhibited superior efficacy compared to 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 unravels the preventive effects of THBru on obesity through the activation of PGC1α-mediated thermogenesis, thereby delineating its potential therapeutic implications for obesity and associated disorders.
肥胖症的不断上升的流行率带来了巨大的挑战，需要开发有效的治疗策略。在这项研究中，我们旨在阐明四氢小檗红碱（THBru）对肥胖的预防作用，THBru 是黄连素（BBR）的衍生物，并揭示其潜在的机制。使用高脂肪饮食（HFD）诱导的肥胖小鼠模型，发现 THBru 可显著改善肥胖，表现为体重减轻、Lee 指数降低、附睾白色脂肪组织（WAT）和棕色脂肪组织（BAT）中的脂肪质量减少，以及血脂异常改善。值得注意的是，在相同剂量下，THBru 比 BBR 具有更好的疗效。RNA 测序和基因集富集分析表明，THBru 激活了产热，这在 WAT、BAT 和 3T3-L1 细胞中得到了进一步证实。RNA 测序数据的生物信息学分析揭示了候选基因 Pgc1α，它是参与产热的关键调节因子。此外，THBru 通过稳定 WAT、BAT 和 3T3-L1 细胞中的其 mRNA 来提高 Pgc1α 的表达。此外，PGC1α 敲低阻断了 THBru 在体内和体外的促产热和抗肥胖作用。这项研究通过激活 PGC1α 介导的产热来阐明 THBru 对肥胖的预防作用，从而为肥胖症及其相关疾病的治疗提供了潜在的意义。
