CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress.

Early on, corticotropin-releasing factor (CRF), a hallmark brain peptide mediating many components of the stress response, was shown to affect food intake inducing a robust anorexigenic response when injected into the rodent brain. Subsequently, other members of the CRF signaling family have been identified, namely urocortin (Ucn) 1, Ucn 2, and Ucn 3 which were also shown to decrease food intake upon central or peripheral injection. However, the kinetics of feeding suppression was different with an early decrease following intracerebroventricular injection of CRF and a delayed action of Ucns contrasting with the early onset after systemic injection. CRF and Ucns bind to two distinct G-protein coupled membrane receptors, the CRF1 and CRF2. New pharmacological tools such as highly selective peptide CRF1 or CRF2 agonists or antagonists along with genetic knock-in or knock-out models have allowed delineating the primary role of CRF2 involved in the anorexic response to exogenous administration of CRF and Ucns. Several stressors trigger behavioral changes including suppression of feeding behavior which are mediated by brain CRF receptor activation. The present review will highlight the state-of-knowledge on the effects and mechanisms of action of CRF/Ucns-CRF1/2 signaling under basal conditions and the role in the alterations of food intake in response to stress

Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study.

Stressors of different psychological, physical or immune origin play a critical role in the pathophysiology of irritable bowel syndrome participating in symptoms onset, clinical presentation as well as treatment outcome. Experimental stress models applying a variety of acute and chronic exteroceptive or interoceptive stressors have been developed to target different periods throughout the lifespan of animals to assess the vulnerability, the trigger and perpetuating factors determining stress influence on visceral sensitivity and interactions within the brain-gut axis. Recent evidence points towards adequate construct and face validity of experimental models developed with respect to animals' age, sex, strain differences and specific methodological aspects such as non-invasive monitoring of visceromotor response to colorectal distension as being essential in successful identification and evaluation of novel therapeutic targets aimed at reducing stress-related alterations in visceral sensitivity. Underlying mechanisms of stress-induced modulation of visceral pain involve a combination of peripheral, spinal and supraspinal sensitization based on the nature of the stressors and dysregulation of descending pathways that modulate nociceptive transmission or stress-related analgesic response

Chemoprevention of aberrant crypt foci in the colon of rats by dietary onion

Onion intake might reduce the risk of colorectal cancer, according to epidemiology. However, Femia showed in 2003 that diets with a 20% onion intake increase carcinogenesis in rats. We speculated this dose was too high. Prevention of initiation was thus tested in 60 rats given a 5% dried onion diet or AIN76 diet, and initiated 12 days later with azoxymethane (AOM, 1 × 20 mg/kg i.p.), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ, 2 × 200 mg/kg p.o.), or N-nitroso–N–methylurea (2 × 50 mg/kg p.o.). Prevention of promotion was tested in 38 rats given AOM, then randomised to: AIN76 diet; 5% onion diet; phytochemicals diet (supplemented with propyl-disulfide, quercetine-glycosides and oligofructose); 1% pluronic F68 diet (a potent chemopreventive PEG-like block-polymer, used as a positive control). Aberrant crypt foci (ACF) were scored 30 days (initiation) or 100 days (promotion) after carcinogen injection. The onion diet given during initiation reduced the number of AOM-induced ACF (60 versus 86, p = 0.03), and the size of IQ-induced ACF (1.33 versus 1.97, p = 0.02). Given post-initiation, the onion diet reduced the number of ACF (34 versus 59, p = 0.008) and of large ACF (6 versus 15, p = 0.02). Phytochemicals diet and pluronic diet reduced ACF growth similarly. Data show that a 5% onion diet reduced carcinogenesis during initiation and promotion stages, and suggest this chemoprevention is due to known phytochemicals

Glycemic index, nutrient density, and promotion of aberrant crypt foci in rat colon

We speculated that a diet with a high glycemic index (GI), or a diet with a low nutrient density (nutrient-to-calorie ratio), would enhance colon carcinogenesis, presuma-bly via increased insulin resistance. Forty-eight female Sprague -Dawley rats (SD) received an azoxymethane injection (20mg /kg) and were randomized to 5 groups given an AIN76 diet containing (1) 65% starch by wt. (2) 65% glucose, GI=100, (3) 65% fructose, GI=23, (4) 82% starch, or (5) 39% oil and 39% sucrose. The nutrient density was halved in 4﷓5 diets compared to 1﷓3 diets. Promotion was assessed by the multi-plicity (number of crypts) of aberrant crypt foci (ACF), an early marker of colon carcinogenesis. Insulin resistance was estimated by (blood insulin x blood glucose), by plasma triglycerides, and by visceral fat. To confirm the results in another rat strain, the whole experiment was duplicated in 48 female Fischer F344 rats. Results show that: (i) ACF multiplicity was not different in glucose- and fructose-fed rats (p>0.7): diets with contrasting GI had the same effect on ACF growth. (ii) Diets of low nutrient density increased visceral fat (p<0.05), but reduced the ACF size in F344 (p<0.001, no reduction in SD). (iii) Indirect insulin resistance markers (FIRI index, blood triglycerides, visceral fat) did not correlate with ACF multiplicity. These results do not support the hypothesis that diets with a high glycemic index, or of low nutrient density, or diets that increase some indirect insulin resistance markers, can promote colon carcinogenesis in female rats

Effect of Meat (Beef, Chicken, Bacon) on Rat Colon Carcinogenesis

High intake of red meat or processed meat is associated with increased risk of colon cancer. In contrast, consumption of white meat (chicken) is not associated with risk and might even reduce the occurrence of colorectal cancer. We speculated that a diet containing beef or bacon would increase and a diet containing chicken would decrease colon carcinogenesis in rats. One hundred female Fischer 344 rats were given a single injection of azoxymethane (20 mg/kg i.p.), then randomized to 10 different AIN-76-based diets. Five diets were adjusted to 14% fat and 23% protein and five other diets to 28% fat and 40% protein. Fat and protein were supplied by 1) lard and casein, 2) olive oil and casein, 3) beef, 4) chicken with skin, and 5) bacon. Meat diets contained 30% or 60% freeze-dried fried meat. The diets were given ad libitum for 100 days, then colon tumor promotion was assessed by the multiplicity of aberrant crypt foci [number of crypts per aberrant crypt focus (ACF)]. The ACF multiplicity was nearly the same in all groups, except bacon-fed rats, with no effect of fat and protein level or source (p = 0.7 between 8 groups by analysis of variance). In contrast, compared with lard- and casein-fed controls, the ACF multiplicity was reduced by 12% in rats fed a diet with 30% bacon and by 20% in rats fed a diet with 60% bacon (p < 0.001). The water intake was higher in bacon-fed rats than in controls (p < 0.0001). The concentrations of iron and bile acids in fecal water and total fatty acids in feces changed with diet, but there was no correlation between these concentrations and the ACF multiplicity. Thus the hypothesis that colonic iron, bile acids, or total fatty acids can promote colon tumors is not supported by this study. The results suggest that, in rats, beef does not promote the growth of ACF and chicken does not protect against colon carcinogenesis. A bacon-based diet appears to protect against carcinogenesis, perhaps because bacon contains 5% NaCl and increased the rats' water intak

Insulin Injections Promote the Growth of Aberrant Crypt Foci in the Colon of Rats

The main objective of the present study was to test the hypothesis that exogenous insulin would enhance colon carcinogenesis. Thirty-six female F344 rats, fed ad libitum a low fat rodent chow, received a single azoxymethane injection (20 mg/kg), and were randomized a week later to two groups. Control rats were given 5 days a week a s.c. saline injection, and experimental rats were given ultralente bovine insulin, 20 U/kg. The promoting effect of insulin injections was assessed by the multiplicity (number of crypts) of aberrant crypt foci after 100 d of treatment (72 injections). The rats given insulin ate more and were heavier than controls (215 ± 11 vs. 182 ± 7 g, p<0.001). Insulin injections also increased the amount of abdominal fat, the plasma triglycerides, and the insulinemia, and decreased blood glucose (all p<0.05). The number of aberrant crypt foci was the same in both groups, but their multiplicity was significantly increased by the insulin injections (2.8 ± 0.3 vs. 2.5 ± 0.2 crypt/focus in controls, p=0.007). Besides, the proportion of sialomucin producing foci was higher in insulin injected rats than in controls (p=0.04). These data show that exogenous insulin can promote colon carcinogenesis in rats, and suggest that lifestyle and diets leading to low blood insulin might protect humans against colorectal cancer

Polyethylene glycol, unique among laxatives, suppresses aberrant crypt foci, by elimination of cells.

OBJECTIVE: Polyethylene glycol (PEG), an osmotic laxative, is a potent inhibitor of colon cancer in rats. In a search for the underling mechanisms, the hypothesis that fecal bulking and moisture decrease colon carcinogenesis was tested. We also investigated the PEG effects on crypt cells in vivo. MATERIAL AND METHODS: Fischer 344 rats (n=272) were injected with the colon carcinogen, azoxymethane. They were then randomized to a standard AIN76 diet containing one of 19 laxative agents (5% w/w in most cases): PEG 8000 and other PEG-like compounds, carboxymethylcellulose, polyvinylpyrrolidone, sodium polyacrylate, calcium polycarbophil, karaya gum, psyllium, mannitol, sorbitol, lactulose, propylene glycol, magnesium hydroxide, sodium phosphate, bisacodyl, docusate, and paraffin oil. Aberrant crypt foci (ACF) and fecal values were measured blindly after a 30-day treatment regimen. Proliferation, apoptosis, and the removal of cells from crypts were studied in control and PEG-fed rats using various methods, including TUNEL and fluorescein dextran labeling. RESULTS: PEG 8000 reduced the number of ACF 9-fold in rats (p40-fold) a fecal marker of epitheliolysis in the gut (p<0.001). PEG normalized the percentage of fluorescein dextran labeled cells on the top of ACF (p<0.001). CONCLUSIONS: Among laxatives, only PEG afforded potent chemoprevention. PEG protection was not due to increased fecal bulking, but in all likelihood to the elimination of cells from precancerous lesions