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. 2015 Mar;59(3):533-43.
doi: 10.1002/mnfr.201400621. Epub 2015 Jan 21.

A weekly alternating diet between caloric restriction and medium fat protects the liver from fatty liver development in middle-aged C57BL/6J mice

Fenni Rusli  1 , Mark V Boekschoten, Arantza Aguirre Zubia, Carolien Lute, Michael Müller, Wilma T Steegenga
Affiliations

A weekly alternating diet between caloric restriction and medium fat protects the liver from fatty liver development in middle-aged C57BL/6J mice

Fenni Rusli et al. Mol Nutr Food Res. 2015 Mar.

Abstract

Scope: We investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet.

Methods and results: Nine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight.

Conclusions: Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice.

Keywords: Dietary intervention; Gene expression profile; Metabolic markers; Nonalcoholic fatty liver disease; Steatosis.

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Figures

Figure 1
Figure 1
Beneficial effects of an INT diet regimen on body, WAT, and liver weight, food intake, and glucose tolerance. (A) Weekly measurement of body weight. (B) WAT weight and the ratio to the body weight. (C) Liver weight, ratio to body weight, and liver weight correlation with body and WAT weight. (D) Energy intake measurement at 12 months, daily (left) and weekly (right). (E) Glucose clearance measured by an oral glucose tolerance test. (F) Fasting plasma insulin levels. Error bars reflect standard deviation (SD). *p <0.05; **p < 0.01; ***p < 0.001 versus the INT-fed group.
Figure 2
Figure 2
Hepatic TG, plasma ALT, and AST and liver histology indicated NAFLD development in C- and MF-fed mice, but not in mice exposed to the CR and INT diet. (A) Hepatic TG content. (B) Correlation between hepatic TG and body weight. (C) Plasma ALT. (D) Plasma AST. Error bars reflect SD. *p < 0.05; **p <0.01; ***p < 0.001 versus the INT group. (E) H–E staining and (F) FCF Green and Sirius Red staining of liver sections of animals with a high and low body weight (original magnification 200×).
Figure 3
Figure 3
The INT-fed mice displayed a similar gene expression profile to the C- and MF-exposed mice with similar body weights. (A) A hierarchical clustering plot depicting the liver gene expression profiles similarity of the different diet regimens. The color band under the plot represents the body weight of individual mice in a white-to-red color scale (white = low values, red = high values). Q-PCR analysis on all animals of all dietary intervention groups shows differential expression of genes involved in (B) lipid droplet formation, (C) inflammatory and fibrosis, and (D) macrophage/monocyte recruitment. No statistical difference was found for gene expressions in the INT-fed mice compared to the other intervention groups. Error bars represent SD.
Figure 4
Figure 4
Proposed models for how the fat storage is distributed in WAT and liver. (A) Excess fat is initially stored in WAT, which may expand until a certain threshold. If the lipid-storage capacity is reached, ectopic fat deposition starts to occur in various organs, such as the liver. (B) During the ad libitum feeding week, the excess energy is mainly stored in WAT, but the compensation of deficit energy during the restricted feeding week might be mobilized predominantly from the liver fat storage. This proposed mechanism of an alternating diet may prevent hepatic steatosis development.
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