Pleiotropic effects of rosuvastatin on the glucose metabolism and the subcutaneous and visceral adipose tissue behavior in C57Bl/6 mice

Abstract

The aim of this study was to evaluate whether rosuvastatin (HMG-CoA reductase inhibitor) modulates the carbohydrate and lipid metabolism, the development of non-alcoholic fatty liver disease (NAFLD), and the increase in body mass in a model of diet-induced obesity. Male C57Bl/6 mice (3-months-old) were fed a high-fat diet (HF, 60% lipids) or the standard chow (SC, 10% lipids) for 15 weeks. The animals were then treated with 10 mg/kg/day (HF-R10 group), 20 mg/kg/day (HF-R20), or 40 mg/kg/day (HF-R40) of rosuvastatin for five weeks. The HF diet led to glucose intolerance, insulin resistance, weight gain, increased visceral adiposity with adipocyte hypertrophy, and hepatic steatosis (micro and macrovesicular). The rosuvastatin treatment decreased the adiposity and the adipocyte size in the HF-R10 and HF-R20 groups. In addition, rosuvastatin changed the pattern of fat distribution in the HF-R40 group because more fat was stored subcutaneously than in visceral depots. This redistribution improved the fasting glucose and the glucose intolerance. Rosuvastatin also improved the liver morphology and ultrastructure in a dose-dependent manner. In conclusion, rosuvastatin exerts pleiotropic effects through a dose-dependent improvement of glucose intolerance, insulin sensitivity and NAFLD and changes the fat distribution from visceral to subcutaneous fat depots in a mouse model of diet-induced obesity.

Figure 1

Initial and finish body mass. Mice were fed the standard chow (SC) or a high-fat diet (HF) for 15 weeks. The mice then received five weeks of rosuvastatin at doses of 10 mg/kg/day (HF-R10), 20 mg/kg/day (HF-R20), or 40 mg/kg/day (HF-R40). The symbols indicate a difference compared with [a] the SC group, [b] the HF group, [c] the HF-R10 group and [d] the HF-R20 group.

Figure 2

Pleiotropic effects of rosuvastatin on the liver morphology. Mice were fed the standard chow (SC) or a high-fat diet (HF) for 15 weeks and then received five weeks of rosuvastatin treatment at doses of 10 mg/kg/day (HF-R10), 20 mg/kg/day (HF-R20), or 40 mg/kg/day (HF-R40). (A) Liver weight corrected by tibia length. (B) Hepatic triglyceride content. The symbols indicate a difference compared with [a] the SC group, [b] the HF group and [c] the HF-R10 group.

Figure 3

Liver photomicrographs stained with hematoxylin and eosin (bar = 30 μm). Note the normal liver morphology in the SC group, whereas the HF groups exhibit micro and macrovesicular steatosis. The rosuvastatin treatment ameliorated the steatosis in a dose-dependent manner, as observed in the treated groups: HF-R10, HF-R20 and HF-R40. The arrows indicate the steatosis. The symbols indicate a difference compared with [a] the SC group, [b] the HF group and [c] the HF-R10 group.

Figure 4

Pleiotropic effects of rosuvastatin on the liver ultrastructure. Mice were fed the standard chow (SC) or a high-fat diet (HF) for 15 weeks, followed by five weeks of rosuvastatin treatment at doses of 10 mg/kg/day (HF-R10), 20 mg/kg/day (HF-R20), or 40 mg/kg/day (HF-R40). Numerical density of mitochondria assessed by stereology. Electron micrographs of the liver (bar = 2 μm). The nucleus (N), nucleolus (Nu) and rugous endoplasmic reticulum (RER) are well preserved, and a number of mitochondria (M) are observed in the SC group. The HF mice exhibit severe macrovesicular (star) and microvesicular (arrow) steatosis, unorganized RER and few mitochondria. Microvesicular steatosis is also found in the HF-R10 group. In contrast, the HF-R20 group has a regular cytoarchitecture, a typical number of mitochondria and spread lipid droplets. A regular nucleus, nucleolus and mitochondria, as well as diminished steatosis, are observed in the HF-R40 group. The symbols indicate a difference compared with [a] the SC group, [b] the HF group and [c] the HF-R10 group.

Figure 5

Western blot analyses of hepatic SREBP-1. A representative immunoblot is shown; the quantification of the bands in the immunoblot is shown below. The values are the means ± S.E.M. from five experiments. The symbols indicate a difference compared with [a] the SC group, [b] the HF group and [c] the HF-R10 group.