Treatment with a cholesterol absorption inhibitor (FM-VP4) reduces body mass and adipose accumulation in developing and pre-obese mice

Objective: Disodium ascorbyl phytostanol phosphate (FM-VP4) is a cholesterol absorption inhibitor, a new class in choles-terol-lowering drug. Previous research on the lipid-lowering and anti-atherosclerotic effects of this drug has reported that administration of FM-VP4 results in a decrease in body mass. This study examined the FM-VP4 dose-dependent mass loss in mice and investigated some potential mechanisms by which decreased mass accumulation may have occurred. The effect of FM-VP4 administration on pre-obese mice was also tested. Research Methods and Procedures: We conducted a dose-dependent study on mouse growth, food and water intake, organ mass, femur length, resting metabolic rate (RMR), maximal oxygen consumption under various conditions (VO2swim and VO2heliox), and fecal fat and plasma assessment for cholesterol and non-esterified fatty acids (NEFA) in mice fed a low fat (LF) or high fat (HF) diet, with or without FM-VP4. The ratio of lean to fat body mass of each animal was also assessed using magnetic resonance spectroscopy. To establish the effect of FM-VP4 on preexisting obesity, mice were fed a high fat diet for 57 days, followed by administration of a diet containing 2% (w/w) FM-VP4 for 93 days. Results: Animals exhibit a dose-dependent decline in body mass without a concomitant decrease in food intake, water intake, spleen, heart, or kidney mass, femur length or lean body mass. A dose-dependent trend toward a reduction in fat mass was observed in both high fat and low fat diet groups, becoming significant at a 1 and 2% FM-VP4 dosage (w/w). No FM-VP4 induced change in food or water intake, or resting metabolic rate was observed; however, an increase in VO2swim was observed in the 2% FM-VP4 group over HF control. These findings were also observed in the pre-obese group treated with 2% FM-VP4. Discussion: We found a dose dependent reduction in mass accumulation in mice treated with FM-VP4. This loss of mass is not due to an increase in resting metabolic rate or decreased food or water intake. The only tissues exhibiting a decrease in mass with FM-VP4 treatment are liver and body fat. Fecal fat content increased significantly with FM-VP4 treatment in a dose-dependent manner, suggesting that the treatment reduces mass accumulation through decreased absorption or increased excretion of lipids.