Micelle Sequestrant Polymers as Novel Therapeutics to Treat Obesity
Bradley P. Sullivan1, Jian Qian1, and Cory Berkland1,2
1Department of Pharmaceutical Chemistry, School of Pharmacy, and 2Department of Chemical and Petroleum Engineering, School of Engineering, The University of Kansas, Lawrence, Kansas.
Thirty-five percent of the United States population is classified as overweight or obese. Several options exist to treat obese patients; however, currently available therapies are associated with side effects or poor long term compliance necessitating development of more efficacious and accepted therapeutics for treating obesity. We synthesized and evaluated Micelle Sequestrant Polymers as novel orally dosed non-absorbable molecules that bind intestinal micelles (i.e., dietary triglycerides, bile acids, and cholesterol), which prevents digestive absorption. Fecal elimination of bile acids was increased in mice fed a high fat diet (HFD, 45% kcal from fat) formulated with 0.5% MSP-1 or 0.5% MSP-2, but not 0.5% MSP-3. Interestingly, fecal elimination of triglyceride was increased in mice fed HFD with 0.5% MSP-1 or 0.5% MSP-3, but not 0.5% MSP-2. Of importance, fecal bile acid, fecal triglyceride, and weight loss was increased in mice fed HFD and treated with 300 or 1,500 mg/kg MSP-1 via daily oral gavage for 5-days compared to mice fed HFD given control gavage (H2O), although weight loss in the 300 mg/kg group did not achieve the level of statistical significance. The data suggest that MSPs can bind whole intestinal micelles and enhance fecal elimination of bile acids and triglycerides. Taken together, MSPs may serve as a novel weight loss platform for inhibiting excess caloric intake by preventing absorption of dietary triglycerides. Furthermore, increasing fecal elimination of bile acids may also simultaneously serve as a cholesterol lowering agent by increasing de novo bile acid synthesis, a metabolite of cholesterol.