An intermittent caloric restriction / medium fat diet protects liver from the progression of non-alcoholic fatty liver disease in C57BL/6J mice

Abstract

Background & Aims: In this study, we investigated metabolic and molecular effects of weekly intervening 30% calorie restriction on long term natural progression of non-alcoholic fatty liver disease (NAFLD), which was induced by a medium fat diet. Methods: Male C57BL/6J mice of 9 weeks old received either (1) a control (C), (2) a calorie restricted (CR), (3) a medium fat (MF; 25%fat) or (4) an intermittent diet (ID), a weekly alternating diet consisting of calorie restriction and medium fat diet ad libitum until sacrifice at the age of 12 months. Various metabolic and molecular features of the liver were examined. Results: The ID regimen improved the status of a range of metabolic parameters and showed no progression to NAFLD: proper glucose tolerance, low hepatic triglyceride content, low plasma alanine aminotransferase and no abnormalities in its liver morphological features; similarly to that of CR. In contrast, the metabolic parameters in a number of the C and MF animals indicated development of NAFLD and hepatic fibrosis, which was positively correlated with body weight. Despite the metabolic phenotypes similarity, the liver gene expression profile of ID-fed mice did not reflect that of CR mice and resembled more to C and MF-fed mice with similar low body weight. Conclusions: Our study reveals that ID is beneficial for metabolic health and prevents the development of NAFLD in mice, with a gene expression profile similar to C and MF diet in a body weight-dependent manner. Overall design: Male C57BL/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (ID; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We treated the mice with either solvent (mock treatment) or PPARa agonist, Wy-14,643 (Wy treatment), 6 hours prior to sacrifice. The mock- and Wy-treatment were applied to body weight-matched mice within each diet group. We performed various measurements on metabolic parameters and gene expression analysis. We made a selection of animals for the microarray analysis: from each diet group we took 4 animals with lowest and highest body weight, both the mock- and Wy-treated animals