Jürgenson Monika, Chithanathan Keerthana, Orav Aivar, Jaako Külli, Viil Janeli, Guha Mithu, Kask Kalev, Zharkovsky Alexander
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Tartu University Hospital Joint Laboratory, Tartu University Hospital, Tartu, Estonia.
Front Pharmacol. 2025 Jan 17;15:1505729. doi: 10.3389/fphar.2024.1505729. eCollection 2024.
Obesity is an emerging health problem worldwide as it is associated with increased risk of cardiovascular, metabolic, mental disorders, and cancer. Therapeutic weight management remains one of the options for the treatment of excess weight and associated comorbidities. In this study, the therapeutic potential of elocalcitol, a fluorinated derivative of vitamin D, was studied on the model of high-fat diet (HFD)-induced obesity in mice.
It was demonstrated that co-administration of elocalcitol in the doses 15 ug/kg (i.p.) twice a week for 16 weeks prevented body weight gain by approximately 15%. The significant retardation in the body weight gain was observed already on the second week of elocalcitol treatment. Administration of elocalcitol also reduced visceral and epididymal fat accumulation by 55% and 35%, respectively, metabolic syndrome development, and lipid droplets accumulation in the liver of mice exposed to HFD. In contrast, the administration of cholecalciferol (vitamin D)-a precursor to calcitriol, the biologically active form of vitamin D, did not affect significantly the signs of obesity and metabolic syndrome, suggesting that the anti-obese effects of elocalcitol are not related to the canonical vitamin D receptor (VDR). Further studies have demonstrated that the preventive effect of elocalcitol is associated with the decreased levels of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and upregulation insulin-inducing gene-1 () mRNA expression suggesting that the anti-obese effect of elocalcitol is mediated via inhibition of SREBP-mediated lipogenesis. We also demonstrated that elocalcitol prevents an increase in the expression of proinflammatory cytokines such as interleukin-1 beta (), tumor necrosis factor-alpha (), and interleukin-18 (), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene reduced the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol's reduction of SCAP is at least partly mediated by miR-146a modulation.
The study demonstrates that elocalcitol prevents HFD-induced obesity and metabolic syndrome in mice, likely by inhibiting SREBP-mediated lipogenesis and upregulating miR-146a. These findings provide valuable insights into the anti-obesity mechanisms of fluorinated D-vitamin analogs and suggest potential therapeutic strategies for obesity prevention.
肥胖是一个在全球范围内日益凸显的健康问题，因为它与心血管疾病、代谢紊乱、精神障碍和癌症的风险增加相关。治疗性体重管理仍然是治疗超重及相关合并症的选择之一。在本研究中，我们以高脂饮食（HFD）诱导的小鼠肥胖模型研究了维生素D的氟化衍生物依洛钙醇的治疗潜力。
结果表明，每周两次腹腔注射15微克/千克剂量的依洛钙醇，持续16周，可使体重增加减少约15%。在依洛钙醇治疗的第二周就已观察到体重增加明显减缓。给予依洛钙醇还分别使内脏脂肪和附睾脂肪积聚减少了55%和35%，改善了代谢综合征，并减少了高脂饮食小鼠肝脏中的脂滴积聚。相比之下，给予胆钙化醇（维生素D）——骨化三醇（维生素D的生物活性形式）的前体，并未显著影响肥胖和代谢综合征的体征，这表明依洛钙醇的抗肥胖作用与经典维生素D受体（VDR）无关。进一步研究表明，依洛钙醇的预防作用与固醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）水平降低以及胰岛素诱导基因-1（Insig-1）mRNA表达上调有关，提示依洛钙醇的抗肥胖作用是通过抑制SREBP介导的脂肪生成来介导的。我们还证明，依洛钙醇可防止促炎细胞因子如白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-18（IL-18）的表达增加，且这种作用与微小RNA-146a（miR-146a）上调有关。miR-146a基因缺失减弱了依洛钙醇的抗肥胖作用，并阻止了其对SCAP水平的影响。数据表明，依洛钙醇对SCAP的降低作用至少部分是由miR-146a调节介导的。
该研究表明，依洛钙醇可预防高脂饮食诱导的小鼠肥胖和代谢综合征，可能是通过抑制SREBP介导的脂肪生成和上调miR-146a实现的。这些发现为氟化维生素D类似物的抗肥胖机制提供了有价值的见解，并提示了肥胖预防的潜在治疗策略。
