Dampened Mesolimbic Dopamine Function and Signaling by Saturated but not Monounsaturated Dietary Lipids

Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.     

Increased fat consumption induced by morphine administration in rats

Patterns of caloric intakes and dietary self-selection of the three macronutrients, protein, fat and carbohydrate were examined in male rats following the administration of morphine sulfate (0.0, 1.0, 10.0 and 20.0 mg/kg, IP). Animals were given access to either ground Purina Chow or one of two dietary self-selection regimes, one with a high-fat ration (7.8 kcal/g) and the other with a fat ration isocaloric to the carbohydrate and protein rations (3.8 kcal/g). Animals received morphine injections at the beginning of a six-hour feeding period and nutrient intakes were measured at 1,2,4 and 6 hours postinjection. Similar patterns of macronutrient choice were observed for both animals maintained on the high-fat regime and animals with access to the isocaloric components following morphine injections. As a function of morphine injections, animals on both self-selection regimes increased fat intake while suppressing carbohydrate intake and exhibiting little modifications in protein intake.     

An assessment of the carcinogenic potential of shea oleine in the rat.

Shea oleine, an oil fraction derived from the nut of the tree Butyrospermum parkii, is used as a frying oil. As part of a series of studies, this investigation examined the carcinogenic potential of 15% (w/w) shea oleine in comparison with 15% (w/w) sheanut oil, and palm oil following dietary administration to rats over 104 weeks. The assessment comprised an evaluation of mortality, clinical signs, body weight, food intake, clinical pathology, organ weights and macroscopic and histopathological examination plus tumour type and incidence evaluation. Results showed that shea oleine produced no adverse effects and no evidence of tumorigenic potential compared to other commercially available sheanut and palm oils in the rat. Notable differences were confined to reduced body weight gain and food intake, reduced cholesterol and increased alkaline phosphatase levels, reduced heart weight and an increased incidence of pulmonary lipidosis with shea oleine diets. The latter effect may reflect a naturally lower incidence of this finding with palm oil diets. Tumour findings, specific to shea oleine diets, were restricted to an increase in the number of hepatomas for females, pancreatic exocrine adenomas for males and skin keratoacanthomas for males fed shea oleine diets. The increase in the incidence of hepatomas with treatment was thought to be related to the high fat content of the diets. The incidence of these tumour findings was similar to that given in published data for the Wistar rat, or the 'in house' values for tumour incidence in rats fed high-fat diets. In conclusion, none of the findings in this study were considered to be adverse effects. In comparison with other commercially available edible oils, shea oleine showed no tumorigenic potential following dietary administration at 7.5 g/kg/day in the rat.     

Oxidative DNA damage levels in rats fed low-fat, high-fat, or calorie-restricted diets.

Increased fat and caloric content of the diet has been associated with increased mammary tumor incidence. The dietary modulation of cellular redox state may be one mechanism behind this association. We have examined the effects of changes in dietary fat and caloric intake on the levels of 5-hydroxymethyluracil in DNA from rat liver and mammary gland. Female Fischer 344 rats, 40 days old, were maintained on 3% (low-fat), 5% (control), or 20% (high-fat) corn oil diets for 2 weeks. A fourth group of rats had the same daily fat intake as the control group, but total caloric intake was restricted by 40%. As a measure of oxidative DNA damage, 5-hydroxymethyluracil levels were measured in the DNA extracted from liver and mammary gland by gas chromatography-mass spectrometry. 5-Hydroxymethyluracil levels in the liver DNA of the low-fat, high-fat, and calorie-restricted groups were decreased relative to that of control, but the only significant decrease was in the calorie-restricted group (p less than 0.01). In the mammary gland DNA, statistically significant decreases in damage were found in each group relative to control (p less than 0.05). The relationship between fat in the diet and oxidative stress is thus complex. These results show that changes in dietary intake of both fat and calories can modulate oxidative DNA damage levels, and the effect of diet was more clearly evident in the DNA from mammary gland than in DNA from liver.     

Dietary fat, body weight, and cancer: contributions of studies in rodents to understanding these cancer risk factors in humans

Understanding diet and energy balance as risk factors for breast, colon, and other cancers requires information on the contribution of each factor and of interactions among factors to cancer risk. Rodent models for breast cancer provide extensive data on effects of dietary fat and calories, energy balance, body weight gain, and physical activity on tumor development. Analyses of the combined data from many studies have shown clearly that quality and quantity of dietary fat and energy balance contribute independently to increased mammary gland tumorigenesis. These findings were seen in female rats fed diets high in fat (35-40% of calories) compared to rats fed control diets, with approximately 10% of calories as fat (Fay and Freedman, 1997, Breast Cancer Res. Treat. 46, 215-223). The methods used permit comparison of experimental and epidemiological data, and they may be useful in extrapolating between species and developing public health recommendations. In addition to the contributions of lifetime-diet composition, intake, energy balance, and physical activity to cancer risk, there are questions about the timing and duration of alterations in these factors and about the "dose-response" characteristics of cancer risk to the factors. Endocrine mechanisms may be significant in mammary gland tumor risk, but experimental and epidemiological data indicate that cancers at other sites, such as colon and liver, also are influenced by the factors listed. Other diet and lifestyle factors that influence energy, or specifically fat, metabolism may also affect risk for cancers that are promoted by increased intake of fat and calories. Studies of separate and interactive effects of dietary fat, black tea, weight gain, and mammary gland tumorigenesis (Rogers, et al, 1998, Carcinogenesis 19, 1269-1273) have been analyzed. Using adjustment of carcinogenesis endpoints for body weight, tumor burden, and latency, they were found to be related to weight gain within treatment groups in 2 of 3 experiments.      

Effects of enterostatin (Val-Pro-Asp-Pro-Arg) on fat intake and blood levels of glucose and insulin in rats.

Enterostatin may be involved in the preference for fat and the control of fat intake. Using two different feeding patterns, we observed a change in food intake after injection of enterostatin (VPDPR) into the third ventricle. When rats were adapted to free selection choice between low fat (LF) and high fat (HF) diets, VPDPR inhibited intake of the LF diet at 100, 200 and 800 ng and inhibited intake of the HF diet at 200 ng. The dose-response of HF diet intake to VPDPR was U-shaped. However, even the optimal dose (200 ng), which reduced the intake of both LF and HF diets when both diets were given together, was not effective when the LF diet was given alone. In the present study, VPDPR has also shown to not affect plasma glucose or insulin levels. These results suggest that exogenous VPDPR may inhibit appetite when endogenous enterostatin secretion is increased by ingestion of dietary fat, and that VPDPR has a limited range of effects on feeding behavior. We support the hypothesis that the early satiety sense of VPDPR as an anorectic agent in a central site is directly related to endogenous enterostatin or procolipase levels after fat intake, but not glucose or insulin levels.     

Carnitine palmitoyl transferase-I inhibition is not associated with cardiac hypertrophy in rats fed a high-fat diet

1. Cardiac lipotoxicity is characterized by hypertrophy and contractile dysfunction and can be triggered by impaired mitochondrial fatty acid oxidation and lipid accumulation. The present study investigated the effect of dietary fatty acid intake alone and in combination with inhibition of mitochondrial fatty acid uptake with the carnitine palmitoyl transferase (CPT)-I inhibitor oxfenicine. Long-chain fatty acids activate peroxisome proliferator-activated receptors (PPAR), thus mRNA levels of PPAR target genes were measured. 2. Rats were untreated or given the CPT-I inhibitor oxfenicine (150 mg/kg per day) and were fed for 8 weeks with either: (i) standard low-fat chow (10% of energy from fat); (ii) a long-chain saturated fatty acid diet; (iii) a long-chain unsaturated fatty acid diet; or (iv) a medium-chain fatty acid diet (which bypasses CPT-I). High-fat diets contained 60% of energy from fat. 3. Cardiac triglyceride content was increased in the absence of oxfenicine in the saturated fat group compared with other diets. Oxfenicine treatment further increased cardiac triglyceride stores in the saturated fat group and caused a significant increase in the unsaturated fat group. Despite elevations in triglyceride stores, left ventricular mass, end diastolic volume and systolic function were unaffected. 4. The mRNA levels of PPAR-regulated genes were increased by the high saturated and unsaturated fat diets compared with standard chow or the medium chain fatty acid chow. Oxfenicine did not further upregulate PPARalpha target genes within each dietary treatment group. 5. Taken together, the data suggest that consuming a high-fat diet or inhibiting CPT-I do not result in cardiac hypertrophy or cardiac dysfunction in normal rats.     

Chromium as an Essential Nutrient for Humans

Chromium is an essential nutrient required for sugar and fat metabolism. Normal dietary intake of Cr for humans is suboptimal. The estimated safe and adequate daily dietary intake for Cr is 50 to 200 μg. However, most diets contain less than 60% of the minimum suggested intake of 50 μg. Insufficient dietary intake of Cr leads to signs and symptoms that are similar to those observed for diabetes and cardiovascular diseases. Supplemental Cr given to people with impaired glucose tolerance or diabetes leads to improved blood glucose, insulin, and lipid variables. Chromium has also been shown to improve lean body mass in humans and swine. Response to Cr is dependent upon form and amount of supplemental Cr. Chromium is a nutrient; therefore, it will only be of benefit to those who are marginally or overtly Cr deficient. Trivalent Cr has a very large safety range and there have been no documented signs of Cr toxicity in any of the nutritional studies at levels up to 1 mg per day.     

Dietary fat source influences neuronal mitochondrial monoamine oxidase activity and macronutrient selection in rats

We previously reported that qualitative changes in dietary fat influence certain monoaminergic mediated behaviours such as pain sensitivity and thermoregulation in a cold environment after an amphetamine challenge. The purpose of this study was to further explore the behavioural consequences of alterations in dietary fat intake by examining another behaviour known to be mediated by the monoamines--food intake regulation--and to begin investigating a biochemical link between dietary fat composition and behaviour. Rats were stabilized to 20% (w/w) soybean oil (SBO) or lard diets for 10 days and then allowed to select for protein (PRO) and carbohydrate (CHO) intake. While total food intake was unchanged, rats fed the SBO diet selected lower PRO (3.1 +/- 0.6 vs. 4.9 +/- 0.6 g/day, SBO vs. lard, respectively) and higher CHO (9.6 +/- 0.7 vs. 7.8 +/- 1.2) intakes than those consuming the lard based diet. Comparable differences were seen in a second trial. Current evidence suggests that the regulation of PRO and CHO intake is under serotonergic control. Therefore to determine whether dietary fat is mediating its effect on macronutrient selection via alterations in serotonin (5HT) metabolism, brain stem concentrations of 5HT and its metabolite 5-hydroxyindole acetic acid (5HIAA) and whole brain (minus brain stem) mitochondrial monoamine oxidase (MAO) activity were measured in a separate set of animals fed the SBO or lard diets for 28 days. Vmax of MAO was decreased in rats fed the SBO diets (20.2 +/- 7.4 vs. 27.9 +/- 8.9 nmol/mg prot/20') compared to those fed the lard diets. Km was unaltered by dietary fat fed. The change in activity of MAO was insufficient to alter steady-state levels of 5HT or 5HIAA. We propose that changes in neuronal functioning, induced by altered dietary fat, contributed to the differences seen in PRO and CHO selection.     

Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis

Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes.     

Central and peripheral contributions of endogenous opioid systems to nutrient selection in rats

The contribution of central and peripheral sites to opioid mediation of energy intake and dietary self-selection of the three macronutrients, protein, fat, and carbohydrate, was examined in male rats. Animals given access to either Purina Chow or a self-selection regime were injected with either the opioid antagonist, naltrexone (0.0, 0.1, 1.0, and 5.0 mg/kg, IP), or quarternary naltrexone (0.0, 0.1, 1.0, and 5.0 mg/kg, IP), an opioid antagonist that does not readily enter the central nervous system. Animals received injections at the beginning of an 8-h feeding period, and nutrient intakes were measured at 1, 2, 4, and 8 h postinjection. Naltrexone and its quarternary analogue differed in their effects both on total energy intake and macronutrient selection. Naltrexone led to significant decreases in total energy intake in animals on both dietary regimes, whereas quarternary naltrexone did not modify energy intake of animals given access to either diet. Naltrexone produced a sustained reduction in fat intake and initial decreases in carbohydrate and protein intakes. Quarternary naltrexone did not modify overall energy intake but did lead to modifications in nutrient choice. In contrast to naltrexone, quarternary naltrexone resulted in increased fat intake, decreased carbohydrate intake, and a small reduction in protein intake. These data suggest that both peripheral and central sites contribute to opioid effects on patterns of nutrient choice.     

Differential effects of amphetamine and fenfluramine on dietary self-selection in rats

Daily caloric intakes and dietary self-selection of the three macronutrients, protein, fat and carbohydrate were examined in female rats following administration of d-amphetamine sulfate (0.0, 0.5, 1.0 and 2.0 mg/kg, IP) or fenfluramine hydrochloride (0.0, 1.5, 3.0 and 6.0 mg/kg, IP). Animals were maintained on ground Purina Chow or one of two self-selection regimes, one with a high-caloric fat ration (7.85 kcal/g) and the other with a fat ration isocaloric to the carbohydrate and protein rations (3.76 kcal/g). Animals received drug injections at the beginning of a daily 8-hour feeding period with nutrient intakes measured at 2, 4 and 8 hrs following injections. While both amphetamine and fenfluramine led to dose-related decreases in total caloric intakes, the two drugs resulted in different temporal patterns of feeding. Amphetamine produced its greatest effect on caloric intake during the first 2 hours of the feeding period, whereas fenfluramine suppressed caloric intake equivalently across the 8-hour feeding period. The two anorectic drugs also led to different patterns of nutrient choice. When animals were given the high-caloric fat ration, amphetamine selectively decreased fat intake while fenfluramine produced decreases in both protein and fat intakes, sparing carbohydrate intake. In contrast, when animals were given the isocaloric fat ration, amphetamine resulted in a general suppression of nutrient intakes while fenfluramine led to a sustained decrease in fat intake with a relative sparing of protein and carbohydrate consumption.     

Effects of dietary poly-unsaturated fatty acids on tracheal histaminergic and cholinergic responsiveness in experimental models of bronchial hypersensitivity and hyperreactivity

Respiratory histaminergic and cholinergic receptor function was investigated in isolated tracheal spirals of guinea pigs receiving different diets. Comparison was made between saline treated (controls) and Haemophilus influenzae treated animals in non sensitized conditions, the latter being a model for bronchial hyperreactivity, and in sensitized conditions, being a model for allergen induced bronchial hypersensitivity. The different semi-synthetic diets (35 energy% fat), varying in linoleic acid content (5.85, 11.25 and 22.05 en% fat) and one diet with low linoleic acid (3.55 en%) in which linolenic acid was added additionally (5.30 en%), exerted profound effects on tracheal reactivity to histamine. In sensitized animals the maximal induced histamine contraction was significantly diminished in the dietary group receiving 5.85 en% linoleic acid as compared with the other dietary groups (35% decrease in the H. influenzae-treated, 20-30% decrease in saline treated animals). Results in non-sensitized animals were similar, though less pronounced. No effect on food intake or growth of the animals could be demonstrated during the six week experimental periods. The carbachol induced contraction of the tracheal spirals of sensitized animals receiving low linoleic acid was also significantly decreased as compared to the other dietary groups (30% for saline treated and 20-30% for H. influenzae-treated animals). No difference in carbachol responsiveness could be detected between the different dietary groups under non-sensitized conditions. The results are discussed in view of the current concepts for bronchial hyperreactivity, especially in relation to eicosanoid involvement.     

Modulation of N-nitrosomethylurea induced mammary tumorigenesis by dietary fat and voluntary exercise.

The effect of dietary fat and exercise on N-nitrosomethylurea [NMU:CAS:684-93-5]-induced mammary tumorigenesis in female F344 rats was investigated. Rats were fed the NIH-07 diet until NMU administration on day 50 of age, when they were transferred to four treatment groups. Three sedentary groups were fed either high-fat (20% wt/wt), medium fat (10%) or low fat (5%) diets (HF, MF, LF, respectively), and a fourth group was fed a HF diet but allowed free access to an activity wheel (HFEX). Tumor yields among the three sedentary groups were significantly greater in the HF and MF groups when compared to the LF group. Voluntary exercise reduced tumor yields and delayed time of tumor appearance in HFEX animals to levels similar to those found in LF sedentary animals. Animals with voluntary access to exercise wheels averaged between 1.03 and 2.85 miles/day, consumed more food (+ 18%) and exhibited greater weight gain (+ 13%) than their sedentary counterparts. No differences in weight gains were detected among the HF, MF, and LF groups, despite widely varying amounts of fat intake. Body composition studies indicated that body fat content was not influenced by the quantity of fat consumed in the diet, but was significantly reduced by voluntary exercise (-20%). Since exercise and fat intake have been associated with alterations in endocrine status, circulating bioactive and immunoactive prolactin were assessed at termination. No significant changes were found in either form of prolactin among the four experimental groups, casting doubt on mediation by this pituitary hormone.     

Neonatal parathion exposure disrupts serotonin and dopamine synaptic function in rat brain regions: Modulation by a high-fat diet in adulthood

The consequences of exposure to developmental neurotoxicants are influenced by environmental factors. In the present study, we examined the role of dietary fat intake. We administered parathion to neonatal rats and then evaluated whether a high-fat diet begun in adulthood could modulate the persistent effects on 5HT and DA systems. Neonatal rats received parathion on postnatal days 1–4 at 0.1 or 0.2 mg/kg/day, straddling the cholinesterase inhibition threshold. In adulthood, half the animals in each exposure group were given a high-fat diet for 8 weeks. We assessed 5HT and DA concentrations and turnover in brain regions containing their respective cell bodies and projections. In addition, we monitored 5HT_1A and 5HT₂ receptor binding and the concentration of 5HT presynaptic transporters. Neonatal parathion exposure evoked widespread increases in neurotransmitter turnover, indicative of presynaptic hyperactivity, further augmented by 5HT receptor upregulation. In control rats, consumption of a high-fat diet recapitulated many of the changes seen with neonatal parathion exposure; the effects represented convergent mechanisms, since the high-fat diet often obtunded further increases caused by parathion. Neonatal parathion exposure causes lasting hyperactivity of 5HT and DA systems accompanied by 5HT receptor upregulation, consistent with “miswiring” of neuronal projections. A high-fat diet obtunds the effect of parathion, in part by eliciting similar changes itself. Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence of neurodevelopmental disorders.     

Effects of chronic ethanol administration in the rat: relative dependency on dietary lipids--III. In vivo tolerance to hexobarbital.

Chronic administration of ethanol with either a high-fat (35% cal., including 2% cal. as linoleate) or a low-fat (2% cal. as linoleate) diet reduces similarly the hexobarbital sleeping times in the rat. Ethanol decreased the plasma and total body half-lives of hexobarbital in both dietary models, but they were decreased significantly more with the high-fat diet. A good correlation between hexobarbital plasma half-life and sleeping time was found only with the high-fat dietary model; the sleeping time was not a good index of hexobarbital metabolism in the low-fat model. Ethanol-fed rats awaken with significantly higher hexobarbital concentrations in brain and other tissues; this phenomenon is significantly more important in the high-fat model. Ethanol, administered chronically in nutritionally adequate liquid diets, increases tolerance to hexobarbital by increasing drug disposition and by decreasing central nervous system sensitivity. Both factors in tolerance are altered by modifications of the dietary lipid intake.     

The effects of dietary protein,fat and 2-acetylaminofluorene on the microsomal activity levels of liver from BALB/c mice

Weanling female BALB/c mice were continuously fed diets containing combinations of 12 or 24% protein, 4 or 24% corn oil and 0 or 500 ppm 2-acetylaminofluorene (2-AAF) for approx. 77 weeks to determine the effects of protein, fat and 2-AAF on the biological activity of hepatic microsomal preparations. The S-9 fractions prepared from the livers of the animals were tested in the Ames mutagenicity assay system using Salmonella typhimurium TA-1538 as the indicator strain.The data showed that animals maintained on high fat diets had significantly lower hepatic microsomal activity levels as measured in the in vitro test. In this experiment, the concentration of dietary protein did not affect the activity levels, but 2-AAF was shown to be a strong inducer of hepatic microsomal activity regardless of the other dietary constituents.     

Induction of gene pattern changes associated with dysfunctional lipid metabolism induced by dietary fat and exposure to a persistent organic pollutant

Environmental modulators of chronic diseases can include nutrition, lifestyle, as well as exposure to environmental toxicants such as persistent organic pollutants. A study was designed to explore gene expression changes as affected by both dietary fat and exposure to the polychlorinated biphenyl PCB77. Mice were fed for 4 months diets enriched with high-linoleic acid oils (20% and 40% as calories), and during the last 2 months half of each group was exposed to PCB77. Ribonucleic acids (RNA) were extracted from liver tissue to determine gene expression changes using DNA microarray analysis. Our microarray data demonstrated a significant interaction between dietary fat and PCB exposure. Deregulated genes were organized into patterns describing the interaction of diet and PCB exposure. Annotation of the deregulated genes matching these probe sets revealed a significant high-fat mediated induction of genes associated with fatty acid metabolism, triacylglycerol synthesis and cholesterol catabolism, which was down-regulated in animals exposed to PCB77. Many of these genes are regulated by the peroxisome proliferator activated receptor-α (PPARα), and changes in PPARα gene expression followed the same gene pattern as described above. These results provide insight into molecular mechanisms of how dietary fat can interact with environmental pollutants to compromise lipid metabolism.     

Dietary high-fat lard intake induces thyroid dysfunction and abnormal morphology in rats

Aim:

Excess dietary fat intake can induce lipotoxicity in non-adipose tissues. The aim of this study was to observe the effects of dietary high-fat lard intake on thyroid in rats.

Methods:

Male Sprague-Dawley rats were fed a high-fat lard diet for 24 weeks, and then the rats were fed a normal control diet (acute dietary modification) or the high-fat lard diet for another 6 weeks. The serum lipid profile, total thyroxine (TT4), free thyroxine (FT4) and thyrotropin (TSH) levels were determined at the 12, 18, 24 and 30 weeks. High-frequency ultrasound scanning of the thyroid glands was performed at the 24 or 30 weeks. After the rats were sacrificed, the thyroid glands were collected for histological and immunohistochemical analyses.

Results:

The high-fat lard diet significantly increased triglyceride levels in both the serum and thyroid, and decreased serum TT4 and FT4 levels in parallel with elevated serum TSH levels. Ultrasonic imaging revealed enlarged thyroid glands with lowered echotexture and relatively heterogeneous features in the high-fat lard fed rats. The thyroid glands from the high-fat lard fed rats exhibited enlarged follicle cavities and flattened follicular epithelial cells under light microscopy, and dilated endoplasmic reticulum cisternae, twisted nuclei, fewer microvilli and secretory vesicles under transmission electron microscopy. Furthermore, the thyroid glands from the high-fat lard fed rats showed markedly low levels of thyroid hormone synthesis-related proteins TTF-1 and NIS. Acute dietary modification by withdrawal of the high-fat lard diet for 6 weeks failed to ameliorate the high-fat lard diet-induced thyroid changes.

Conclusion:

Dietary high-fat lard intake induces significant thyroid dysfunction and abnormal morphology in rats, which can not be corrected by short-term dietary modification.     

Effect of varying caloric restriction levels on female rat growth and 5-hydroxymethyl-2'-deoxyuridine in DNA.

Caloric restriction has previously been shown to decrease levels of oxidative stress in rats. In this study, we examined the effects of 5 different caloric intake levels on one type of oxidative DNA damage in rat mammary gland, blood, and liver. Animals were fed modified AIN-93G diets to accommodate 10, 20, 30, or 40% calorie restriction (CR), relative to ad libitum (AL) consumption. The intakes of fat, protein, vitamins, and minerals thus remained constant, but total carbohydrate intake decreased. Body weights of the animals at 20 weeks reflected the degree of restriction, but in the first 10 weeks, weight gain in the 10% CR group was not reduced relative to animals fed ad libitum. Levels of 5-hydroxymethyl-2'-deoxyuridine increased with time in mammary gland and nucleated blood cells regardless of CR level, indicating an effect of animal age, despite the fact that the animals were only 7 months old after the 20-week dietary study. In liver, however, there was a trend towards decreased DNA damage levels with time. The effect of diet on levels of 5-hydroxymethyl-2'-deoxyuridine was not statistically significant, indicating no protective effect of restricted dietary carbohydrate. This dietary study differed from previous work in that the modified AIN-93G dietary formulation contains relatively higher levels of fat and vitamins K, E, and B(12), and it has certain added trace minerals. This data raises the question of whether the previously reported effects of calorie restriction on preventing oxidative stress in mammary gland are dependent on the type of dietary formulation used.