Monika Jürgenson ¹ Keerthana Chithanathan ¹ Aivar Orav ² Külli Jaako ¹ Janeli Viil ¹ Mithu Guha ¹ Kalev Kask ³ Aleksandr Zarkovski ^1*

• ¹ Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
• ² Tartu University Hospital's joint laboratory, Tartu, Estonia
• ³ Adge Pharmaceuticals Inc, Mountain View, CA, United States

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 (Insig1) 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 (Il1b), tumor necrosis factor-alpha (Tnf), and interleukin-18 (Il18), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene largely diminished the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol induced reduction in SCAP at least in part, influenced by the modulation of miR-146a expression. These findings open new avenues of research for a better understanding of the possible mechanism of anti-obese action of fluorinated D-vitamin analogs and potential new therapeutic strategies for the prevention of obesity.