Food-restricted Group Research Articles

Food restriction in young Japanese quails: effects on growth, metabolism,plasma thyroid hormones and mRNA species in the thyroid hormone signalling pathway

Young birds, in their post-natal growth period, may reduce their growth and metabolism when facing a food shortage. To examine how such responses can be mediated by endocrine-related factors, we exposed Japanese quail chicks to food restriction for either 2 days (age 6-8 days) or 5 days (age 6-11 days). We then measured growth and resting metabolic rate (RMR), and circulating 3,3',5-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4) levels as well as expression patterns of genes involved in growth (insulin-like growth factor-I: IGF-I) and thyroid hormone signalling (thyroid-stimulating hormone-beta: TSHbeta, type II iodothyronine deiodinase: D2, thyroid hormone receptors isoforms: TRalpha and TRbeta). The food-restricted chicks receiving a weight-maintenance diet showed reductions in structural growth and RMR. Plasma levels of both T3 and T4 were reduced in the food-restricted birds, and within the 5 days food-restricted group there was a positive correlation between RMR and T3. IGF-I mRNA showed significantly higher abundance in the liver of ad libitum fed birds at day 8 compared with food-restricted birds. In the brain, TSHbeta mRNA level tended to be lower in food-restricted quails on day 8 compared with controls. Furthermore, TRalpha expression was lower in the brain of food-restricted birds at day 8 compared with birds fed ad libitum. Interestingly, brain D2 mRNA was negatively correlated with plasma T3 levels, tending to increase with the length of food restriction. Overall, our results show that food restriction produced significant effects on circulating thyroid hormones and differentially affected mRNA species in the thyroid hormone signalling pathway. Thus, we conclude that the effects of food restriction observed on growth and metabolism were partly mediated by changes in the endocrine-related factors investigated.

Lipid peroxidation and antioxidant status in rat: effect of food restriction and wheel running

Using the activity-based anorexia model, the aim of this investigation was to explore antioxidant enzyme activity (catalase, superoxide dismutase), total antioxidant status (TAS), and alpha-tocopherol in blood, liver, and gastrocnemius muscle associated with the food restriction and voluntary wheel running during 8 days. In addition, lipid peroxidation was measured by measurements of malondialdehyde (MDA). Wistars rats (n = 56) were randomly assigned to one of four groups: an ad lib sedentary group, a control wheel activity group, a food restriction-induced hyperactivity group (1 h/day ad lib food, 23 h/day ad lib wheel access), and a food-restricted sedentary group. The animals were killed when the rats in the food-restricted group had lost 25% of their free feeding weight. Antioxidant enzyme activities and TAS in blood, liver, and gastrocnemius muscle were unaffected by voluntary wheel running. A wheel activity effect (P < 0.05) was obtained for the MDA concentrations in plasma, with lower concentrations in trained animals. Food restriction effects were obtained for antioxidant capacity in liver, as well as for CAT activity in the gastrocnemius muscle and plasma MDA concentrations with lower values in the restricted animals. On the other hand, the food-restricted rats showed higher plasma TAS concentrations (P < 0.05) and higher alpha-tocopherol concentrations in the liver (P < 0.05) when compared to animals fed ad libitum. Our results also showed that food restriction coupled to wheel running decreased antioxidant parameters in liver, and plasmatic MDA concentrations and increased TAS plasma concentrations when compared to the ad libitum sedentary situation.

Food restriction promotes downregulation of myocardial L-type Ca2+ channels

Food restriction (FR) has been shown to impair myocardial performance. However, the mechanisms behind these changes in myocardial function due to FR remain unknown. Since myocardial L-type Ca2+ channels may contribute to the cardiac dysfunction, we examined the influence of FR on L-type Ca2+ channels. Male 60-day-old Wistar rats were fed a control or a restricted diet (daily intake reduced to 50% of the amount of food consumed by the control group) for 90 days. Myocardial performance was evaluated in isolated left ventricular papillary muscles. The function of myocardial L-type Ca2+ channels was determined by using a pharmacological Ca2+ channel blocker, and changes in the number of channels were evaluated by mRNA and protein expression. FR decreased final body weights, as well as weights of the left and right ventricles. The Ca2+ channel blocker diltiazem promoted a higher blockade on developed tension in FR groups than in controls. The protein content of L-type Ca2+ channels was significantly diminished in FR rats, whereas the mRNA expression was similar between groups. These results suggest that the myocardial dysfunction observed in previous studies with FR animals could be caused by downregulation of L-type Ca2+ channels.

Comparison of the effects of food versus protein restriction on selected nutritional and inflammatory markers in rats

We previously demonstrated that feeding a 2% protein AIN-76 diet ad libitum for 14 days resulted in substantial clinical and biochemical changes including weight loss, hypoglycemia, hypoalbuminemia, higher levels of plasma cytokines, oxidative stress in the liver, and activation of inflammatory signaling to interleukin (IL)-6, as compared with a 20% protein diet. In the present study, 54 rats were randomly given a standard rat chow diet ad libitum, or a 25% or 50% reduction of this intake for 14 days. The results showed that weight gain was less in the 25% food-restricted group and halted in the 50% group as compared with the control group. Unlike protein restriction, neither level of food restriction altered plasma levels of albumin and glucose, the hepatic protein abundance of signal transducers and activators of transcriptions and of mitogen-activated protein kinases, or the hepatic contents of total glutathione and malondialdehyde. The intracellular signaling in response to IL-6 stimulation was also well maintained. However, both levels of food restriction elevated IL-1 and corticosterone in plasma, did not alter ghrelin, and decreased plasma levels of free fatty acids. Because these latter 3 markers were not examined previously, 20 rats were fed an AIN-76 diet, either with 20% or 2% protein, ad libitum for 14 days. The 2% protein diet significantly decreased plasma levels of free fatty acids and increased ghrelin and corticosterone as compared with the 20% protein diet. Thus, food restriction, where all essential nutrients are reduced in proportion, is a physiologic stress that, while limiting growth, does not activate or impair the systemic inflammatory response, whereas a very low protein diet with little change in energy intake has a substantial impact on systemic inflammation, body composition, and growth.

Effect of Food Availability on Immune Function of Gray Red-Backed Voles (Myodes rufocanus) Exposed to Low Temperature and Short Photoperiod

The effects of food availability on immune function of gray red-backed voles (Myodes rufocanus) exposed to low temperature (5°C) were examined under a short photoperiod (10L:14D). Twenty-seven voles, caught in the wild, were evenly divided into 3 groups adjusted for sample size, body mass, and sex ratio. Among the 3 food-manipulation groups (food control, food addition, and food restriction), the food-added group displayed enhanced immune response. In contrast, the food-restricted group displayed weakened immune response and the lowest body mass. Kidneys, hearts, and livers of food-restricted voles were significantly hypertrophied in comparison with food-control voles and food-added voles. Therefore, food limitation (quality and quantity) may cause a reduction in immune function and body mass at low temperature on short photoperiods because of maximum expenditure of acquired resources for thermoregulation and maintenance of body condition and, consequently, may induce higher mortality during cold and long winters.

Changes in plasma and tissue amino acid levels in an animal model of complex fatigue

Objective Fatigue can be classified as physical or mental, depending on its cause. In physical fatigue, changes in the plasma levels of some amino acids have been reported. However, complex fatigue, which is experienced in daily life, is a combination of physical and mental fatigue. We aimed to identify changes in amino acid levels in the plasma, skeletal muscle, liver, and brain in an animal model of complex fatigue. Methods Rats were kept in a cage filled with water to a height of 2.2 cm for 5 d. Because rats showed a reduction of body weight when the model was developed, we also included a food-restricted group showing a similar profile in weight reduction as the water-immersed rats. A non-treated control group was also included. Results Results indicated that levels of branched-chain amino acids (valine, leucine, and isoleucine) were increased in plasma (valine, leucine, and isoleucine; P < 0.01), skeletal muscle (valine, leucine, and isoleucine; P < 0.01), the liver (valine; P < 0.05), and brain (isoleucine; P < 0.05), whereas a reduction in other amino acid levels (total amino acids and glutamine in the plasma, skeletal muscle, and liver; and phenylalanine, tyrosine, arginine, and threonine in the brain; P < 0.01) was seen in animals with complex fatigue. Conclusion Complex fatigue may bring about systemic changes in amino acid metabolism in multiple organs.

Effect of intrauterine undernutrition during late gestation on pancreatic β cell mass

We analyzed the effect of low birth weight on pancreatic beta cell mass. We used pregnant C57BL6J mice, and we reduced their food supply by 30% during the late gestational period and examined the changes in the metabolism and pancreatic beta cell mass. Pancreatic beta cell mass at birth was greatly decreased in the mice of the food restriction group (RG) as compared to the mice of the control group (CG). The body weight of RG mice exhibited a "catch-up growth" pattern and became equivalent to that of CG mice 7 days after birth, and thereafter exceeded that of CG mice; however, the pancreatic beta cell mass in RG mice remained lower than that in CG mice at the age of 4 weeks. A high-fat diet significantly increased the pancreatic beta cell mass in RG mice as compared to that in CG mice at 12 weeks of age. However, RG mice fed on high-fat diets tended to exhibit a decrease in the pancreatic beta cell mass at approximately 20 weeks of age. The plasma insulin concentrations also tended to be decreased in RG mice after 24 weeks of age as compared to those of CG mice. These results thus indicate that the growth of pancreatic beta cells is insufficient in RG mice, and pancreatic beta cell failure can easily develop as a consequence of insulin resistance.

Gene Expression Profiles in Fetal and Neonatal Rat Offspring of Energy-Restricted Dams

Background/Aims: Nutrition during fetal and early postnatal development can have permanent effects on physiology resulting in an increased risk for disease in later life. The aim of this study was to explore changes in gene expression related to maternal energy restriction during pregnancy in rat fetuses and in neonatal rat offspring. Methods: From day 4 of gestation until parturition, energy-restricted dams received either 75 or 50% of ad libitum food intake. Microarray analyses were performed on whole 13- and 17-day fetuses and 1-day-old pups. Protein and fat contents of the dams’ milk were analyzed in the different feeding groups. Results: A surprisingly small number of genes were differentially expressed between the groups, probably due to the strict control of fetal development. Interestingly, the expressions of many pancreatic digestion enzymes were reduced in the 1-day-old pups of the energy-restricted dams. A statistically significant difference in milk protein content was observed on day 1 post-partum between the gestationally food-restricted groups. Conclusions: The expressions of several genes that may have an important role in the normal development of organs were affected by undernutrition during fetal development. In addition, undernutrition may have affected the function of the exocrine pancreas.

The effect of energy restriction during pregnancy on obesity-related peptide hormones in rat offspring

It has been proposed that fetal exposure to environmental stressors, such as undernutrition, during critical periods of development may lead to adaptations that permanently change the structure and function of the body. These adaptations may be important for immediate survival during fetal development, but can predispose to disease in later life. We designed a pilot study investigating the effect of fetal undernutrition on the obesity-related peptides adiponectin, ghrelin, leptin and resistin levels in rat. We also wanted to explore changes in lipid and insulin metabolism. Sprague–Dawley rats were randomly assigned to three dietary treatment groups on day 4 of gestation. The control group was fed ad libitum and the food-restricted rats received either 75% or 50% of ad libitum food intake until parturition. Serum levels of obesity-related peptides as well as lipid and insulin levels were measured from 1-month-old pups. Serum resistin concentrations were higher in both food-restricted groups and serum adiponectin concentration was lower in the 50% food-restricted group compared to the control group. Serum total cholesterol levels were significantly higher in both food-restricted groups. These results indicate that undernutrition during fetal development may lead to unfavorable changes in obesity-related peptide hormones as well as evoking adverse changes in serum cholesterol levels. The observed changes may predispose to insulin resistance and significantly increase the risk of developing cardiovascular disease in later life.

Evaluation of body development, fat mass and lipid profile in rats fed with high-PUFA and -MUFA diets, after neonatal malnutrition

Neonatal malnutrition is associated with several features of the metabolic syndrome, later in life. Although the recovery of malnutrition was studied with different high-fat diets, few studies compare the effects of enriched vegetable oil diets, containing PUFA and MUFA, after weaning. Our aim was to evaluate the recovery with soya oil- or rapeseed oil-enriched diet, after malnutrition in rats whose mothers were food restricted (FR) during lactation. Dams were 50 % FR and compared to standard diet-fed dams (control, C). At 21 d, FR offspring had a lower body mass and length. After weaning C and FR offspring were fed a diet containing 7 % soya oil (7 %sC and 7 %sFR), or supplemented with 19 % soya oil (19 %sC or 19 %sFR) or 19 % rapeseed oil (19 %cC or 19 %cFR). The normal animals fed enriched vegetable oil diets had more visceral fat mass, but lower serum TAG and higher HDL-cholesterol. The 19 %FR groups showed significantly less food intake and body development compared to the 7 %sFR, and the same pattern was observed when this group was compared to the C groups. Absolute and relative mass of vital organs and body were lower in the FR groups. Visceral fat depot was lower in 19 %FR than 7 %FR and C groups. Serum glucose, albumin, TAG, cholesterol, leptin and triiodothyronine did not show significant changes. However, 19 %FR groups showed higher HDL-cholesterol and the 19 %sFR group showed lower serum thyroxine. The data suggest that a higher vegetable oil diet in the recovery of neonatal malnutrition ameliorates some features of the metabolic syndrome later in life.

Food restriction impairs myocardial inotropic response to calcium and β-adrenergic stimulation in spontaneously hypertensive rats

Although long-term food restriction (FR) has been shown to induce cardiac remodeling and dysfunction, there are few data on the effects of FR on pressure-overloaded hearts. The aim of this study was to examine the effects of FR on cardiac muscle performance during inotropic stimulation in the myocardium of spontaneously hypertensive rats (SHRs). Male 60-day-old SHRs were subjected to FR for 90 days. Food-restricted animals received 50% of the ad libitum amount of food consumed by the control group. Myocardial function was studied in isolated left ventricular papillary muscle under isometric contraction in basal condition (1.25 mmol/L extracellular Ca(2+) concentration) and after 3 inotropic maneuvers: (1) at postrest contraction of 30 seconds, (2) at extracellular Ca(2+) concentration of 5.2 mmol/L, and (3) after beta-adrenergic stimulation with 10(-6) mol/L isoproterenol. At basal condition, time from peak tension to 50% relaxation was greater in the food-restricted group (P < .05). Inotropic stimulation with postrest contraction and isoproterenol promoted a significant lower increase of developed tension, maximum rate of tension development, and maximum rate of tension decline in the food-restricted compared to the control group. The elevation of extracellular Ca(2+) concentration induced a lower increase of developed tension, maximum rate of tension development, and time from peak tension to 50% relaxation in the food-restricted than in the control group. In conclusion, long-term FR promotes impairment of myocardial inotropic response to calcium and beta-adrenergic stimulation in SHRs.

Effect of Silymarin on Metabolic Factors of Food-Restricted Over Conditioned Wistar Rats

This study was conducted to evaluate the changes in serum metabolic factors of over conditioned pregnant rats treated with silymarin in food restriction condition. Sixty pregnant Wistar rats were divided into five equal groups. All rats received high energy diet before treatments. Control group were fed ad libitum (Non-FR). Rats in other groups received 50% of the food intake of Non-FR group and served as food-restricted (FR) groups. Three of five FR groups received 150, 200 and 400 mg kg(-1) silymarin, respectively (FR-150, 200, 400). Another FR group (FR-Con) and the Non-FR group did not receive any silymarin. Glucose, triglyceride, LDL and HDL cholesterol, total cholesterol, thyroid hormones and cortisol were measured in serum. All factors were significantly different between groups except free-T4 and T4. Serum glucose concentrations in FR-150 and 200 and Non-FR groups were lower than FR-Con and FR-400. Silymarin significantly increased serum triglycerides, LDL cholesterol and cholesterol contents in FR groups. The highest levels of these factors were noted in 200 mg silymarin-treated group. HDL cholesterol was highest in FR-Con; meanwhile FR-200 group had the lowest HDL cholesterol. Serum cortisol decreased in treated and untreated FR groups except FR-150 group. Free-T3 and T3 concentrations in FR-400 and FR-Con groups were higher than the other silymarin treated groups. In conclusion our results indicate that 200 mg kg(-1) of silymarin in Wistar rats is the best dosage to achieve metabolic benefits. Silymarin has positive effects on lipid metabolism and can modulate serum triglyceride and cholesterol concentrations in food restriction condition. Also, the present findings suggest that silymarin under food restriction situation exerts a decreasing effect upon peripheral conversion of T4 to T3.

Reply to: Schreuder

reply: In aging male Wistar rats, renal injury develops spontaneously ([2][1]). It is gratifying that Dr. Schreuder is intrigued by our recent finding of a protective effect of early postnatal protein restriction (i.e., during lactation) on the spontaneous development of renal injury in male Wistar

Maternal care in white-tailed deer: trade-off between maintenance and reproduction under food restriction

Lactation is the most energetically costly component of maternal investment in mammals. For large temperate herbivores, summer is characterized by relatively abundant forage but also high energetic needs for lactation and recovery from winter mass loss. We experimentally restricted food supply by about 20%, and compared the nursing and foraging behaviours of control and food-restricted adult female white-tailed deer, Odocoileus virginianus, and their fawns during lactation. We considered two fawn ages: 0–30 days (after which time spent suckling dropped markedly) and 30–80 days (the end of the nursing period). From 0 to 30 days of age, food-restricted fawns performed 17 more suckling bouts/day and spent twice as much time suckling than control fawns. Compared with controls, food-restricted fawns gained 26% less mass from birth to 80 days. Body growth was inversely related to time spent suckling and to the frequency of nursing bouts, but positively related to survival. Food-restricted fawns had twice as many suckling solicitations and rejected suckling attempts as control fawns. Solicitations for allosuckling and successful allosuckling bouts were also more than twice as high in the food-restricted group as in the control group. Mothers and fawns from the food-restricted group spent more time foraging than control individuals. We conclude that a reduction in food availability during summer, which may occur under high intraspecific competition, should lead to drastic changes in foraging and nursing behaviours as well as reduced growth rate of juveniles of large northern herbivores.

Food restriction in pregnant and lactating rats induces anemia and increases plasma lipid peroxidation in their progeny

This study was designed to investigate the effects of food restriction in female rats during pregnancy and lactation periods on hematologic parameters in their progeny. Twelve pregnant Wistar rats were randomly divided into 2 groups: a control (C) group with free access to a standard diet and a food-restricted group with alternating 24 hours of fasting and nonfasting from day 14 of pregnancy to day 14 of lactation. Food restriction reduced the number of red blood cells, hemoglobin concentration, and hematocrit values in mothers and their pups. In dams, plasma iron and folate levels were respectively reduced by 27% (P < .04) and 46% (P < .01) compared with the C group, whereas plasma copper and vitamin B12 levels were unchanged. In pups, plasma iron, copper, and vitamin B12 levels were decreased by 50%, 23%, and 16%, respectively, compared with those in the C group, whereas folate levels were unchanged. Blood glutathione levels were significantly decreased in mothers and pups compared with those in the C group. Erythrocyte osmotic fragility decreased, and plasma thiobarbituric acid–reactive substance (TBARS) levels increased only in pups. The results of the present study suggest that food restriction in rats provoked alterations in erythrocyte parameters in mothers, probably as a consequence of disturbance in the iron status. In pups, these changes might be pronounced by an increase in TBARS levels and erythrocyte osmotic fragility, which suggests involvement of lipid peroxidation, causing alteration of erythroid cells.

Behavioral and biochemical effects of various food-restriction regimens in the rats

In this paper we describe the effects of six different food restriction (FR) regimens on amphetamine (AMPH)-induced locomotor and nonlocomotor activities in male rats. Changes in serum corticosterone (CORT), insulin and glucose levels were also examined. Each regimen was implemented through different daily food allowance (50%, 25% and 12.5% of the daily food intake, referred to as 50%, 75% and 87.5% FR groups, respectively) and by a specific feeding regimen — either every day (ED) or every other day (EOD). AMPH injection led to a significant increase of locomotor activity in all rats subjected to FR compared to ad libitum fed rats. A significant increase of nonlocomotor activity was observed only in the 75% FR and 87.5% FR groups. The serum CORT levels were significantly elevated and the serum insulin and glucose levels were significantly decreased in all of the FR groups in comparison to the AL rats. The results presented in this paper suggest that the ED regimens produced changes in motor activity and biochemical parameters, which were more-or-less dependent on the degree of FR. In contrast, the EOD regimens induced very similar changes irrespective of the degree of FR degree. Our data support the possible mechanistic roles of CORT and insulin in the effect of FR on locomotor activity, since the most pronounced increase of serum CORT and more pronounced decrease in serum insulin concentration was observed in the groups that also exhibited the highest locomotor activities.

Effect of maternal food restriction during gestation on early development of F1 and F2 offspring in the rat-like hamster ( Cricetulus triton)

Maternal food restriction (FR) may have strong and long-term effects on body weight, brain and behavior development of offspring. However, it is still not well understood whether such an effect is carried over to the next generation. Our objective was to examine the differences of maternal behavior, body growth, cranial growth and early development of F1 and F2 offspring of rat-like hamsters between a FR group and a control group. Results show that FR has a significant influence on maternal gathering behavior. The body weight of F1 offspring was significantly lower in the food-restricted group compared with that of the control animals, while the body weight of food-restricted F2 offspring was not significantly different from that of the control group. The physical development and neurodevelopment of food-restricted F1 and F2 offspring were significantly delayed compared to the controls. These results suggest that FR in female rat-like hamsters affected negatively the body growth of F1 offspring, and the physical and neurodevelopment of both F1 and F2 offspring. The effect of maternal FR on F2 offspring was smaller than that on F1 offspring. These factors may, in turn, play an important role in the population regulation of this species.

Chronic food restriction in young rats results in depression- and anxiety-like behaviors with decreased expression of serotonin reuptake transporter

Evidence of semi-starvation is commonly found in patients with eating disorders. This study was conducted to examine the adverse effects of chronic caloric restriction in young rats, since there have been increasing incidence of eating disorders especially among young populations. Food restriction group was supplied daily with 50% of chow consumed by its ad libitum fed control group from postnatal day 28. After 5 weeks of food restriction, brain contents of serotonin (5-hydroxy-tryptamine; 5-HT) and its metabolite 5-hydroxyindol acetic acid were analyzed by high-performance liquid chromatography and mRNA expression of 5-HT reuptake transporter (5-HTT) by in situ hybridization. Plasma corticosterone levels were determined by radioimmunoassay. Behavioral assessments were performed with Porsolt swim test for depressive behavior and with elevated plus maze test for anxiety. Five weeks of food restriction markedly increased plasma level of corticosterone, and significantly decreased 5-HT turnover rates in the hippocampus and the hypothalamus. 5-HTT mRNA expression decreased in the raphe nucleus of food restricted rats compared with free fed controls. Immobility time during the swim test increased in the food restricted group, compared to the control group. Food restricted rats spent more time in the closed arms, less time in the open arms, of elevated plus maze compared with control rats. These results suggest that chronic caloric restriction in young rats may lead to the development of depressive and/or anxiety disorders, likely, in relation with dysfunction of brain 5-HT system.

The effects of food restriction on some biochemical parameters and certain bacterial groups in the cecum in Sprague Dawley rats

Objective: Moderate food restriction, such as a 20-40% reduction of the ad libitum intake without causing malnutrition, delays or prevents morphological and functional changes related to aging and overnutrition. This study was performed to evaluate the effects of moderate to severe food restriction (20%, 40%, and 60% of ad libitum intake) for 28 days on some bacterial groups in the cecum and certain biochemical variables in male Sprague Dawley rats. Materials and methods: One group was allowed free access to food (control), while the others were given food restricted to 20%, 40%, and 60% of the ad libitum consumption for 28 days. At the end of the experiment control and food-restricted animals were sacrificed and cecum weight, pH of cecal contents, and counts of total anaerobes, total aerobes, lactobacilli, and coliform bacteria in cecal contents were determined. Metabolic effects of food restriction were evaluated by analyzing some biochemical parameters in plasma and serum. Results : The effect of 60% restriction was severe; three animals died before the 28th day of experiment in this group. In general, biochemical variables did not change in 20% and 40% food-restricted groups. Although lactobacilli counts of the 20% and 40% restricted groups were significantly increased when compared with the 60% restricted group, none of the three groups were differed from the control group. Furthermore, the total aerobe bacteria counts of the 20% restricted group were significantly lower than those of the 60% restricted group. Conclusion: The results of this study suggest that restriction of food by 20% and 40% may affect cecal microbiota beneficially without causing considerable changes in the metabolism of the host, while 60% restriction causes dietary stress. Key words: food restriction, starvation, malnutrition, rat, cecal microbiota, biochemical variables

The role of food restriction on CCl 4-induced cirrhosis model in rats

Effects of food restriction on susceptibility to the toxic effect of some chemicals are controversial. In order to identify an exposure model that could maximize cirrhosis and minimize mortality rate, this study aimed to evaluate the effect of food restriction on tetrachloride carbon (CCl 4)-induced cirrhosis model in rats. Fifty-three male Wistar rats received CCl 4 0.25 ml/kg weekly intragastrically once a week. Thirty-three had 44% food restriction (group 1); 10 rats had 25% food restriction (group 2); and 10 rats received ad libitum food (group 3). After 10 weeks, the animals were sacrificed and liver sections were collected for histology. Of the 53 animals enrolled for the study, 22 (41.5%) died before completing 10-week CCl 4. Mortality rate was significantly higher in group 1 compared to other groups ( p<0.05). Cirrhosis was significantly more prevalent in group 1 than in group 3 ( p<0.01), but without significant difference between groups 1 and 2 ( p=0.624). We concluded that food restriction is an important issue to be considered when establishing a CCl 4-induced cirrhosis model in rats. Moreover, there is an ideal range of food intake that predisposes to liver damage without increasing mortality leading to a more effective model.