Session: FP03-Glucocorticoids & Glucocorticoid Actions
Room 130 (Moscone Center)
Poster Board SAT-4
Production of the glucocorticoid cortisol is regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11bHSD1) in the adipose tissue and liver, and its excess is associated with accumulation of visceral fat and development of insulin resistance in human. 11bHSD1 (-/-) mice fed a high-fat diet exhibit reduced visceral fat accumulation and improved insulin sensitivity in adipose tissue. We investigated in this study the effects of a novel selective (IC50:3.8 nM) 11bHSD1 inhibitor, DSP-0011, on triglycerides (TG) accumulation in human adipocytes, body fat mass and insulin sensitivity in diet-induced-obese (DIO) mice. In addition, we developed a DIO common marmoset (C. marmoset) model, and evaluated the effect of our compound on fat distribution in the model.
Materials and methods:
The effect of DSP-0011 on TG accumulation in human adipocytes was evaluated using the Oil Red O staining method. The in vivo effects of DSP-0011 were assessed by conversion of prednisone to prednisolone instead of conversion of endogenous glucocorticoids.DIO mice were administered DSP-0011 (10, 30 and 100 mg/kg) once daily for 10 weeks and subjected to Oral Glucose Tolerance Test (OGTT) after the final dosing. The weight of visceral fat was also measured in these mice. DIO C. marmosets were administered DSP-0011 (200 mg/kg) once daily for 4 weeks, and the volumes of visceral and subcutaneous fat were measured by micro CT. The concentration of plasma adiponectin was also determined by LC-MS.
DSP-0011 reduced TG accumulation in human adipocytes as indicated by decreased Oil Red O stained area (IC50: 230 nM). In vivo, DSP-0011 dose-dependently inhibited 11bHSD1-mediated conversion of prednisone to prednisolone in both mice (94% inhibition at 6 hr after administration of DSP-0011 at 30 mg/kg) and C. marmosets (76% inhibition at 6 hr after administration of DSP-0011 at 200 mg/kg). In DIO mice, DSP-0011 dose-dependently decreased both the area under the curve of plasma insulin level and the weight mesenteric fat. In DIO C.marmosets, DSP-0011 decreased visceral fat mass with little effects on body weight and food intake. Furthermore, DSP-0011 increased plasma total adiponectin.
Our results show that DSP-0011 can ameliorate insulin resistance not only in DIO mice but also in DIO C. marmosets mainly by reduction of visceral fat mass. DSP-0011 is therefore expected to treat metabolic syndrome caused by visceral fat accumulation. The DIO model in nonhuman primate C. marmosets could be useful to predict clinical efficacy more accurately.
Nothing to Disclose: TG, JN, YH, YS, TI, YH, HS, NK, TN, AT, RH, HK
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