Despite the relatively large number of publications in the area of ACC inhibition, there have been few disclosures reporting the effects of long-term administration of ACC inhibitors on metabolic syndrome-related endpoints. Recently, two disclosures reported the results of studies of the balanced ACC1/ACC2 inhibitor 2 in mouse models of metabolic syndrome [48,49]. In the first study, 2 was administered in chow to ob/ob mice at doses of 50 and 100 mg/kg for 8 weeks. Treatment with 2 resulted in increased glucose and triglyceride levels and decreased insulin levels in blood. The AUC and peak glucose response in an oral glucose tolerance test (OGTT) were also increased. After 6 weeks, the 100 mg/kg dose group was lowered to 20 mg/kg. This resulted in normalization of triglyceride and glucose levels, but insulin levels remained low. Body weight decreased in the 100 mg/kg dosing group, but food intake remained approximately the same for all the animals in the study. It was concluded that 2 worsened the diabetic phenotype in ob/ob mice, but the authors indicated that the origin of this effect was unclear .
The second study with 2 was performed in diet-induced obese (DIO) C57Bl6/J mice. Compared to control DIO mice, mice treated with 2 showed significantly less weight gain over the course of the 6-week study. However, mice treated with 2 had liver triglyceride and total cholesterol levels that were identical to untreated DIO mice. In a glucose infusion clamp study, the glucose infusion rate was slightly higher for the treated animals (~10%) than for the untreated DIO mice. The study concluded that treatment with 2 had a moderate effect on improving the diabetic phenotype of DIO mice .
In addition to these studies with 2, the effects of the dual ACC1/ ACC2 inhibitor 1 in in vivo efficacy studies in high-fat-fed C57Bl6/J mice have been reported . In mice fed a high-fat chow diet, 1 administered in-diet (50 and 100 mg/kg/day) dose-dependently reduced body weight gain relative to a high-fat chow-fed control group. Mice treated with 1 also had significantly higher levels of p-hydroxybutyrate than the high-fat-fed control group, indicating a shift in energy utilization to increased fatty acid metabolism in these mice. Additionally, fasting plasma insulin levels were lower in mice treated with 1 than in the high-fat control group, and in a glucose infusion rate study, mice dosed with 1 showed an improved response relative to the high-fat mice. Interestingly, the level of hepatic malonyl-CoA was found to be lower in the group dosed with 50 mg/kg of 1 than it was in the animals that were fed normal chow, while animals receiving 100 mg/kg of 1 had identical malonyl-CoA levels to the animals fed normal chow. The study concluded that treatment with 1 resulted in favorable effects on diabetic symptoms in DIO mice.
Was this article helpful?
A Hard Hitting, Powerhouse E-book That Is Guaranteed To Change The Way You Look At Your Health And Wellness... Forever. Everything You Know About Health And Wellness Is Going To Change, Discover How You Can Enjoy Great Health Without Going Through Extreme Workouts Or Horrendous Diets.