Effect of wheat bran on excretion of radioactively labeled estradiol-17 beta and estrone-glucuronide injected intravenously in male rats.

Urinary and fecal estrogen excretion were studied in male rats fed a non-fiber wheat starch diet (dietary fiber less than 1%; NF group; n = 4), a low-fiber wheat flour diet (dietary fiber 2%; LF group; n = 4) or a high-fiber wheat bran diet (dietary fiber 11.6%; HF group; n = 3). Short-term effects of the experimental diet on estrogen excretion were studied after i.v. injection of 5 microCi (0.185 MBq) of [14C]estradiol-17 beta (E2) into the tail vein of the rats fed the diets for 2 days. After 3 weeks on the experimental diets, the long-term effects were studied after injection of 5 microCi of [14C]E2 and 10 microCi of [3H]estrone-3-glucuronide (E1-gluc). The diet was found to affect estrogen excretion. The short-term effect indicated that rats fed the HF diet excreted a relatively large amount of labeled compounds in the feces during the first day after injection, while rats fed the NF or the LF diets excreted about half that amount over the same period. On the other hand, urinary excretion of labeled compounds was significantly higher in the NF and LF rats. The long-term effect resulted in steeper slopes (P less than 0.05) of the fecal excretion profiles of rats fed the HF diet as compared with rats fed the NF and LF diets, indicating an accelerated fecal excretion of labeled compounds in the HF rats. The kinetic profiles of 14C and 3H radioactivity in blood plasma indicated a fast decrease (t1/2 of less than 2 min) for both [14C]E2 and [3H]E1-gluc. It was concluded that, owing to the short-term effect of wheat bran intake, during the first 24 h after i.v. administration relatively large amounts of radioactively labeled compounds are excreted in feces of rats fed the HF diet. In contrast, excretion is lower in urine of these rats. When the microflora is adapted to the experimental diet the wheat bran diet still results in an accelerated fecal excretion of labeled compounds, which might be attributed to an interruption of the enterohepatic circulation of estrogens. This might result in lowered plasma and/or tissue estrogen levels and hence a decreased exposure of estrogen-sensitive tissue to estrogens, which might decrease risk on mammary (breast) cancer development.     

Fish oil supplementation increases expression of mammary tumor apoptosis mediators and reduces inflammation in an obesity-associated HER-2 breast cancer model

Obesity is associated with inflammation and has been shown to increase breast cancer severity. The objective of this study was to examine the effect of fish oil (FO) supplementation in obesity-associated mammary tumorigenesis in the MMTV-neu(ndl)-YD5 mouse model of human epidermal growth factor receptor-2 positive BC. Female mice were fed one of three diets for 16 weeks: i) high fat diet [HF, % kacl: 41.2% lard, 18.7% corn oil (CO)], ii) an isocaloric HF plus menhaden FO diet (HF+FO, % kcal: 41.2 lard, 13.4% CO, 5.3% FO), iii) low fat diet (LF, % kcal: 4.7% lard, 6% CO). HF mice had increased body weight, visceral adipose weight and serum hormone concentrations (increased leptin and resistin; decreased adiponectin) versus LF, which was attenuated in the HF+FO group versus HF (P<.05). Compared to HF, tumor onset was delayed in HF+FO and LF mice (P<0.05). Compared to HF, HF+FO reduced mammary tumor multiplicity (-27%), tumor weight (-46%) and total tumor volume (-50%) (P<0.05). Additionally, HF+FO reduced mammary tumor multiplicity (-33%), tumor weight (-39%) and total tumor volume (-60%) versus LF. HF+FO improved mammary tumor apoptosis status with increased expression of pro-apoptotic Bad and decreased expression of anti-apoptotic Bcl-xLmediators versus HF (P<0.05). Additionally, HF+FO decreased tumor protein expression of activated Akt, NFκB p65 and STAT3, versus HF (P<0.05). Tumor mRNA expression of inflammatory mediators TNFα, IL-6 and leptin were reduced in HF+FO, whereas IL-10 expression was increased compared to HF (P<0.05). Collectively these results demonstrate the efficacy of FO supplementation for improving obesity-associated breast cancer outcomes.     

Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during the fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a highfat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in tne serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high fat diet. Furthermore, the administration of estradiol to pregnant dams produce effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.     

Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats

The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.     

Marie Ménard apples with high polyphenol content and a low-fat diet reduce 1,2-dimethylhydrazine-induced colon carcinogenesis in rats: Effects on inflammation and apoptosis

Inflammation may increase cancer risk, therefore, we studied whether polyphenol-rich Marie Ménard (MM) apples with reported anti-inflammatory activity prevent 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats and, likewise whether high-fat (HF) diet promoting carcinogenesis, may affect inflammation. DMH-induced rats were fed for 15 weeks with: an HF diet (23% corn oil w/w); an HF diet containing 7.6% w/w lyophilized MM (apple diet (AD)); a low-fat (LF) diet and an HF diet containing piroxicam (PXC) (0.01% w/w) as control. Mucin depleted foci (MDF), precancerous lesions in the colon, were dramatically reduced in the AD, LF, and PXC groups compared with the HF. Peritoneal macrophage activation, an index of systemic inflammation, was significantly decreased in the AD, LF, and PXC groups. TNF-α, iNOS, IL-1β, IL-6 m-RNA expression in the colon, as well as CD68 cells and plasmatic PGE2 were lower in the AD, but not in the LF group. Apoptosis in the MDF of both the AD and LF-fed rats was significantly higher than in HF rats. In conclusion, AD has a strong chemopreventive effect, reducing inflammation, and increasing apoptosis, while the chemopreventive effect of the LF diet seems mediated mainly by increased apoptosis in MDF.     

Effects of estrogen on gender-related autonomic differences in humans

Our previous studies demonstrated that premenopausal women have dominant vagal and subordinate sympathetic activity compared with age-matched men. This study was designed to investigate the role of estrogen in gender-related autonomic differences. We evaluated the heart rate variability of four healthy groups: age-matched postmenopausal women without hormone replacement therapy (PM), postmenopausal women on conjugated estrogen replacement therapy (PME), men, and non-age-matched premenopausal women (PreM). Frequency-domain analysis of short-term and stationary R-R intervals was performed to evaluate low-frequency power (LF; 0.04-0.15 Hz), high-frequency power (HF; 0.15-0.40 Hz), the ratio of LF to HF (LF/HF), and LF in normalized units (LF%). No gender-related autonomic differences existed between the PM and men groups, but they did exist between the PME and men group. Compared with the PreM group, the PM group had a lower HF and higher LF% and LF/HF. Compared with the PM group, the PME group had a higher HF but lower LF% and LF/HF. These results suggest that conjugated estrogen replacement therapy may facilitate vagal and attenuate sympathetic regulation of heart rate in postmenopausal women. In addition, estrogen may play an important role in gender-related autonomic differences.     

Soluble Fermentable Dietary Fibre (Pectin) Decreases Caloric Intake,Adiposity and Lipidaemia in High-Fat Diet-Induced Obese Rats

Consumption of a high fat diet promotes obesity and poor metabolic health, both of which may be improved by decreasing caloric intake. Satiety-inducing ingredients such as dietary fibre may be beneficial and this study investigates in diet-induced obese (DIO) rats the effects of high or low fat diet with or without soluble fermentable fibre (pectin). In two independently replicated experiments, young adult male DIO rats that had been reared on high fat diet (HF; 45% energy from fat) were given HF, low fat diet (LF; 10% energy from fat), HF with 10% w/w pectin (HF+P), or LF with 10% w/w pectin (LF+P) ad libitum for 4 weeks (n = 8/group/experiment). Food intake, body weight, body composition (by magnetic resonance imaging), plasma hormones, and plasma and liver lipid concentrations were measured. Caloric intake and body weight gain were greatest in HF, lower in LF and HF+P, and lowest in the LF+P group. Body fat mass increased in HF, was maintained in LF, but decreased significantly in LF+P and HF+P groups. Final plasma leptin, insulin, total cholesterol and triglycerides were lower, and plasma satiety hormone PYY concentrations were higher, in LF+P and HF+P than in LF and HF groups, respectively. Total fat and triglyceride concentrations in liver were greatest in HF, lower in LF and HF+P, and lowest in the LF+P group. Therefore, the inclusion of soluble fibre in a high fat (or low fat) diet promoted increased satiety and decreased caloric intake, weight gain, adiposity, lipidaemia, leptinaemia and insulinaemia. These data support the potential of fermentable dietary fibre for weight loss and improving metabolic health in obesity.     

Diminished satiation in rats exposed to elevated levels of endogenous or exogenous cholecystokinin

Rats maintained on a high-fat (HF) diet exhibit reduced sensitivity to the satiation-producing effect of exogenous CCK. Because more CCK is released in response to HF meals than low-fat (LF) meals, we hypothesized that increased circulating CCK associated with ingestion of HF diets contributes to the development of decreased CCK sensitivity. To test this hypothesis, we implanted osmotic minipumps filled with either NaCl or CCK octapeptide into the peritoneal cavity. Subsequently, we examined the effect of intraperitoneal NaCl or CCK (0.5 microg/kg) injection on 30-min food intake. CCK significantly reduced 30-min food intake less in rats implanted with CCK-releasing minipumps compared with those with NaCl-releasing minipumps. Because dietary protein is a potent releaser of endogenous CCK, we hypothesized that rats adapted to a high-protein (HP) diet might also exhibit reduced sensitivity to exogenous CCK. Therefore, in a second experiment, we examined CCK-induced reduction of food intake in rats maintained on LF and rats maintained on HF or HP. Ingestion of LF stimulates very little endogenous CCK secretion, whereas both HF and HP markedly increase plasma CCK concentrations. Both doses of CCK reduced food intake significantly less in HF and HP rats compared with LF rats. There were no differences in 24-h food intake, body weight, or body fat composition among LF-, HF-, and HP-fed rats. These results are consistent with the hypothesis that sustained elevation of CCK either by infusion of exogenous CCK or by dietary-induced elevation of plasma CCK contributes to the development of reduced sensitivity to exogenous CCK.     

Obesity induced by a high-fat diet downregulates apolipoprotein A-IV gene expression in rat hypothalamus

Apolipoprotein A-IV (apo A-IV) is an anorectic protein produced in the intestine and brain that has been proposed as a satiety signal. To determine whether diet-induced obesity alters apo A-IV gene expression in the intestine and hypothalamus, rats were fed a high-fat (HF), low-fat (LF), or standard chow (CHOW) diet for 2, 4, 6, 8, or 10 wk. Rats fed the HF diet had significantly greater body weights than rats given the LF and CHOW diets. Intestinal and plasma apo A-IV levels were comparable across dietary groups and time. LF and CHOW rats had comparable hypothalamic apo A-IV mRNA across the course of the experiment. However, HF rats had a slow and progressive diminution in hypothalamic apo A-IV mRNA over time that became significantly lower than that of LF or CHOW rats by 10 wk. Intragastric infusion of lipid emulsion to animals that were fasted overnight significantly stimulated hypothalamic apo A-IV mRNA in LF and CHOW rats but had no effect in HF rats. These results demonstrate that chronic consumption of a HF diet significantly reduces apo A-IV mRNA levels and the response of apo A-IV gene expression to dietary lipids in the hypothalamus. This raises the possibility that dysregulation of hypothalamic apo A-IV could contribute to diet-induced obesity.     

Effect of dietary zinc intake on N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats

Numerous studies have shown that zinc nutrition influences the growth of several types of tumor. However, the influence of zinc nutrition on mammary tumorigenesis is not known. To study the effects of dietary zinc intake on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis, female Sprague-Dawley rats were fed an egg-white-based diet providing 3 (Z3), 12 (Z12), or 31 (Z31) mg zinc/kg diet ad libitum. In addition, two pair-fed controls, PFZ12 and PFZ31, were also included. Fourteen weeks after MNU injection, cumulative tumor incidence and total number of tumors were lower in Z3 rats than in Z12 and Z31 rats. Cumulative tumor incidence and total number of tumors were lower in Z3 rats than in PFZ12 rats, but were the same as in PFZ31 rats. Cumulative tumor incidence and total number of tumors were also lower in pair-fed controls than in their corresponding ad libitum controls, but were the same between the ad libitum controls. Overall, the results showed that the effect of marginal zinc deficiency on MNU-induced mammary tumorigenesis in rats was primarily the result of a reduced feed intake associated with marginal zinc deficiency rather than zinc per se.     

Influence of dietary fat on some metabolic responses of cattle to hyperthermia induced by heat exposure

1. Two breeds of cattle which differ in their plasma concentrations of lipid components (PCLC) and ability to tolerate heat were used to study metabolic responses to hyperthermia. Two maintenance diets, LF (2.5% Fat) and HF (9.2% Fat), which were isonitrogenous and isocaloric were used. 2. The PCLC, the net esterification of cholesterol by the lecithin: cholesterol acyl transferase system and faecal fat excretion were increased by the HF diet which reduced urinary N loss. 3. Hyperthermia disturbed lipid metabolism in all animals and reductions in the concentrations of plasma cholesterol and phospholipid paralleled the increases in the quantities of fat excreted in the faeces. 4. Within breeds the animals on the HF diet maintained a higher PCLC, lower body temperature and conserved more body nitrogen during hyperthermia than animals on the LF diet. 5. The results point to a role for dietary lipid in ameliorating the metabolic disturbances in animals during chronic hyperthermia.     

Antimutagenic effects of wheat bran diet through modification of xenobiotic metabolising enzymes

Diets containing wheat bran (WB) protect against cancers of the colon or breast in rats, and may be beneficial in humans. In a previous study of rats treated with the carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), inclusion of 10% wheat bran in the diet led to an apparent reduction in IQ metabolites but not of intact IQ in plasma. In the present study, male Wistar rats were fed diets containing 0, 10 or 20% wheat bran, and effects on xenobiotic metabolising enzymes compared. Wheat bran-supplementation showed differential effects on phase I enzymes, significantly increasing the activity of hepatic cytochrome P450 isozyme CYP3A2, but slightly reducing the activity of CYP1A1/2. The activities of both hepatic phase II detoxification enzymes glutathione-S-transferase and glucuronosyl transferase were also reduced. Western blotting revealed similar effects on expression of the proteins. Interestingly, the expression of xenobiotic metabolising enzymes (XME) in the colon appeared to be modulated independently of hepatic XME. Although the wheat bran-supplemented diet still led to an increased expression of CYP3A, it now slightly increased CYP1A in the colon. However, 20% wheat bran significantly increased the expression of both glutathione transferase isozymes, GST A1 & A2, in the colon. Natures Gold (NG) is a commercial wheat bran derivative which is lower than wheat bran in dietary fibre, but enriched in vitamins, minerals and various phytochemicals. Dietary supplementation with 20% Natures Gold led to similar trends as seen in wheat bran-fed rats, but more potent effects in both hepatic and colonic enzymes. The significance of these changes for activation of carcinogens to mutagenic metabolites was investigated using the Salmonella/mammalian microsome mutagenicity test. The activation of IQ and benzo[a]pyrene, but not cyclophosphamide, to a mutagen by hepatic S9 from wheat bran-fed or Natures Gold-fed rats was significantly reduced compared with S9 from animals on a diet lacking wheat bran. We suggest that modulation of xenobiotic metabolising enzymes may be an important component of cancer protection by wheat bran, and this effect may relate to micronutrients or cancer-protective non-nutrient phytochemicals rather more than to dietary fibre.     

Suppression of QRFP 43 in the hypothalamic ventromedial nucleus of Long-Evans rats fed a high-fat diet

QRFP 43 is a RFamide peptide present in the ventromedial nucleus (VMN) and lateral hypothalamus. It stimulates food intake in mice and its chronic infusion induces hyperphagia, reduced thermogenesis, and obesity. In this experiment, we measured it in the VMN and lateral hypothalamus of Long-Evans rats fed either a high-fat (HF), control, or low-fat (LF) diet in parallel with plasma leptin, adiposity, and energy intake. After 8 weeks of ad libitum diet intake, energy intake of HF rats was similar to that of control rats. In the VMN, QRFP 43 was completely undetectable in HF rats and its tissue concentration in control rats was significantly lower than in LF rats (p < 0.03). HF rats had higher levels of leptin than control rats (+24%; p < 0.03) and than LF rats (+42%; p < 0.002). The QRFP 43 concentration in the VMN was inversely correlated with plasma leptin (r = −0.34; P < 0.04) and with the adipogenic index of the diet (p < 0.02) but not with insulin. We conclude that the decrease of the orexigenic drive mediated by QRFP 43 could contribute to the normalization of caloric intake in HF diet fed rats. QRFP 43 might play a role downstream of leptin in the regulation of feeding behavior.     

Urinary estrogen profile determination in young Finnish vegetarian and omnivorous women

For a long time it has been postulated that diet may influence estrogen metabolism and in this way affect breast cancer risk. In order to investigate possible effects of variations of dietary fiber intake on estrogen metabolism, the urinary estrogen profile (13 estrogens), including the catecholestrogens, was determined in one 72-h summer and one winter sample collected in the midfollicular phase of the menstrual cycle by 11 lactovegetarian and 12 omnivorous young Finnish women. Urinary estrogens were purified by ion-exchange chromatography and the quantitative determination was carried out by capillary gas chromatography-mass spectrometry. Detailed records of the subjects' diet during one 5-day period in summer and one in winter were obtained and dietary fiber intake calculated. The mean difference with regard to intake of total fiber in the two dietary groups was 3 g/day in the summer (not significant) and 5 g/day in the winter (P less than 0.05), the mean (geometric) consumption being 23 and 19 g/day by the vegetarian and omnivorous women, respectively. Within the groups we found seasonal variation in fiber intake only for the omnivorous women. During winter, compared to summer, the omnivorous women consumed significantly less grain (P less than 0.001), vegetable (P less than 0.02) and total fiber (P less than 0.02). The excretion of 13 estrogens was remarkably constant in the omnivoric group but a significant seasonal variation of total and individual catecholestrogens and of estrone was observed in the vegetarians (P less than 0.05-0.005). The quantitatively most important estrogen was 2-hydroxyestrone, followed by estrone, estriol, 2-hydroxyestradiol, 4-hydroxyestrone and estradiol, the three latter being excreted in similar amounts. Between the dietary groups there were no significant differences in excretion of total or individual urinary estrogens in any season or between the mean values for both seasons. However, numerous significant (P less than 0.05-0.01) negative correlations between dietary intake of total or grain fiber/kg body weight and the excretion of individual estrogens were found. These correlations disappeared if the fiber intake was not related to body weight. We conclude that dietary fiber intake significantly affects estrogen metabolism by reducing estrogen excretion in urine and that grain fiber seems to be most important in that respect. One of the mechanisms involved is a partial interruption of the enterohepatic circulation of the estrogens, due to alterations of the intestinal metabolism and reabsorption of these steroids, caused by the fiber.     

Interactions of dietary fat and 2,5-anhydro-D-mannitol on energy metabolism in isolated rat hepatocytes

The fructose analog 2,5-anhydro-D-mannitol (2,5-AM) stimulates feeding in rats by reducing ATP content in the liver. These behavioral and metabolic effects occur with rats fed a high-carbohydrate/low-fat (HC/LF) diet, but they are prevented or attenuated when the animals eat high-fat/low-carbohydrate (HF/LC) food. To examine the metabolic bases for this effect of diet, we assessed the actions of 2,5-AM on ATP content, oxygen consumption, and substrate oxidation in isolated hepatocytes from rats fed one of the two diets. Compared with cells from rats fed the HC/LF diet ("HC/LF" cells), cells from rats fed the HF/LC diet ("HF/LC" cells) had similar ATP contents but lower oxygen consumption, decreased fructose, and increased palmitate oxidation. 2,5-AM did not decrease ATP content or oxygen consumption in HF/LC cells as much as it did in HC/LF hepatocytes, and it only affected fructose and palmitate oxidation in HC/LF cells. 31P-NMR spectroscopy indicated that differences in phosphate trapping accounted for differences in depletion of ATP by 2,5-AM. These results suggest that intake of the HF/LC diet prevents the eating response and attenuates the decline in liver ATP by shifting hepatocyte metabolism to favor fat over carbohydrate as an energy-yielding substrate.     

Carcinogenicity and hormone studies with the tissue‐selective estrogen receptor modulator bazadoxifene

Bazedoxifene Acetate (BZA) is a selective estrogen receptor modulator (SERM) that is approved for the prevention and/or treatment of osteoporosis in postmenopausal women. To assess for carcinogenic potential, BZA was administered ad libitum in the diet to rats for 2 years. BZA caused an increase in benign ovarian tumors in female rats and decreased incidences of mammary tumors (females) and pituitary tumors (males and females). In addition, BZA provided a significant survival benefit at all dosages tested, which correlated with a significant reduction in pituitary and mammary gland tumors and decreased body weight gain (both genders). Additional studies were subsequently conducted in rats and monkeys to further explore the mechanisms likely responsible for the observed effects. Results from studies in hypophysectomized and chemically castrated female rats indicated that BZA did not directly stimulate formation of ovarian cysts, but an intact pituitary was required for cyst formation. Further, BZA increased estradiol concentrations in rats and monkeys. In monkeys, BZA increased concentrations of luteinizing hormone (LH) after onset of treatment and prohibited the preovulatory surge of LH until after cessation of treatment. These hormonal changes suggest that BZA inhibited both the positive and negative feedback effects of estrogen on gonadotropins and the resulting increase in LH caused formation and persistence of ovarian cysts, which eventually transformed into benign ovarian granulosa cell tumors in the rat carcinogenicity study. These results also suggest that the reductions in pituitary and mammary gland tumors were attributed to BZA‐related antagonism of endogenous estrogens at the estrogen receptors. J. Cell. Physiol. 228: 724–733, 2013. © 2012 Wiley Periodicals, Inc.     

Intragastric beta-casomorphin(1-7) attenuates the suppression of fat intake by enterostatin

The current experiments were designed to compare the feeding response to enterostatin and beta-casomorphin(1-7) injected intragastrically. Sprague-Dawley rats with a gastric cannula were allowed to chose from high-fat diet (HF) or low-fat diet (LF) in separate jars. Enterostatin injected intragastrically into overnight fasted rats caused a U-shaped dose-dependent reduction in the intake of the HF diet for the first two hours after infusion but had no effect on the LF intake. beta-Casomorphin(1-7) stimulated the intake of the HF diet but had no effect on the LF diet. Finally, beta-casomorphin(1-7) blocked the inhibitory effect of enterostatin on HF intake in fasted rats.     

Influence of caloric restriction and exercise on tumorigenesis in rats

Underfeeding or caloric restriction have been shown to inhibit the growth of spontaneous, transplanted, or chemically induced tumors in rats and mice. At 40% caloric restriction, growth of 7,12-dimethylbenz(a)anthracene-induced mammary and 1,2-dimethylhydrazine-induced colonic tumors is inhibited significantly even when the restricted diet contains twice as much fat as the control diet. Some inhibitory effects become evident even at 10% caloric restriction. In studies involving high fat diets, we find that rats receiving 20% fat ad libitum exhibit significantly higher 7,12-dimethylbenz(a)anthracene-induced mammary tumor incidence, multiplicity, and weight than rats ingesting the same amount of fat daily, but in a diet containing 25% fewer calories. In a study of intermittent ad libitum and restrictive feedings, chemically induced tumorigenicity varies inversely with feed efficiency. Exercise has also been shown to inhibit tumor growth. Sedentary rats fed ad libitum have a 108% higher incidence of 1,2-dimethylhydrazine-induced colon tumors than rats fed ad libitum but subjected to vigorous treadmill exercise. Caloric flux (either reduced intake or increased outflow) appears to reduce tumorigenicity in rodents.     

Novel application of Shochu distillery by-products to prophylaxis against mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene in rats

The effect of the heat-dried product of Shochu distillery by-products (HSDB) derived from sweet potato on mammary carcinogenesis in rats was investigated. HSDB was fed at 2.5% or 5% of the total feed weight. Dietary HSDB at the 5% level suppressed the incidence and number of tumors, and delayed the latency of mammary tumor development relative to the control diet. Experiments were conducted to determine the relative polarity of the anticarcinogenic constituent(s). The number of tumors per tumor-bearing rat was lower in the diet group fed with an ethyl acetate extract of HSDB than in the control group. The tumor incidence evaluated at both palpation and autopsy was slightly lower in the group fed with a methanol extract than in the control group. These results suggest that HSDB contained at least two constituents of differing polarity that counteracted mammary carcinogenesis.     

Effect of dietary polyunsaturated fat and 7,12-dimethylbenz(a)-anthracene on rat splenic natural killer cells and prostaglandin E synthesis

Summary Dietary polyunsaturated fat has been shown to stimulate mammary tumorigenesis induced in rats by 7,12-dimethylbenz(a)anthracene (DMBA). Studies were undertaken to investigate the effect of polyunsaturated fat and DMBA on splenic natural killer (NK) activity and prostaglandin E (PGE) synthesis. In a first experiment, splenic NK activity at 33, 55, 75, and 110 days of age was measured in Sprague-Dawley rats fed 0.5% low fat (LF), 5% normal fat (NF), or 20% high fat (HF) corn oil diets from 23 days of age. At 55 days of age, half of the rats from the 75 and 110 day age groups were given 5 mg DMBA. Ten days after the initiation of the diets splenic NK activity against YAC-1 lymphoma was decreased from 50% cytotoxicity in rats fed NF diet to 21% cytotoxicity in rats fed HF diet, but was not affected by LF feeding. No difference in NK activity was observed among the groups at the later time periods. DMBA had no effect on NK activity at 20 or 55 days after its administration. In a second experiment, where DMBA (15 mg/rat) was given to half of the rats at 50 days of age and NF or HF diets were started 3 days later, NK activity was 35% in rats fed NF diet and 21% in rats fed HF diet, 5 days after the diets were started. No difference in NK activity in rats fed either diet was observed at later time periods. DMBA decreased both NK activity and spleen cellularity transiently. In both experiments, PGE synthesis by spleen cells cultured for 18 h was not affected by dietary fat intake, but was slightly increased 3 days after DMBA administration. Results from these experiments suggest that the stimulation of DMBA-induced mammary tumorigenesis by polyunsaturated fat and by DMBA itself may possibly be mediated by a transient decrease in splenic NK cell activity.This work was supported by grants CA-35641, CA-33240, CA-13038 and Core Grant CA-24538 from the National Cancer Institute