Reduced CCK signaling in obese-prone rats fed a high fat diet

Deficits in satiation signaling during obesogenic feeding have been proposed to play a role in hyperphagia and weight gain in animals prone to become obese. However, whether this impaired signaling is due to high fat (HF) feeding or to their obese phenotype is still unknown. Therefore, in the current study, we examined the effects of CCK-8 (0.5, 1.0, 2.0, and 4.0 μg/kg) on suppression of food intake of HF-fed obese prone (OP) and resistant (OR) rats. Additionally, we determined the role of endogenous CCK in lipid-induced satiation by measuring plasma CCK levels following a lipid gavage, and tested the effect of pretreatment with devazepide, a CCK-1R antagonist on intragastric lipid-induced satiation. Finally, we examined CCK-1R mRNA levels in the nodose ganglia. We show that OP rats have reduced feeding responses to the low doses of exogenous CCK-8 compared to OR rats. Furthermore, OP rats exhibit deficits in endogenous CCK signaling, as pretreatment with devazepide failed to abolish the reduction in food intake following lipid gavage. These effects were associated with reduced plasma CCK after intragastric lipid in OP but not OR rats. Furthermore, HF feeding resulted in downregulation of CCK-1Rs in the nodose ganglia of OP rats. Collectively, these results demonstrate that HF feeding leads to impairments in lipid-induced CCK satiation signaling in obese-prone rats, potentially contributing to hyperphagia and weight gain.     

Neuronal-glial interactions in rats fed a ketogenic diet

Glucose is the preferred energy substrate for the adult brain. However, during periods of fasting and consumption of a high fat, low carbohydrate (ketogenic) diet, ketone bodies become major brain fuels. The present study was conducted to investigate how the ketogenic diet influences neuronal-glial interactions in amino acid neurotransmitter metabolism. Rats were kept on a standard or ketogenic diet. After 21 days all animals received an injection of [1-(13)C]glucose plus [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from cerebral cortex and plasma were analyzed by (13)C and (1)H nuclear magnetic resonance spectroscopy and HPLC. Increased amounts of valine, leucine and isoleucine and a decreased amount of glutamate were found in the brains of rats receiving the ketogenic diet. Glycolysis was decreased in ketotic rats compared with controls, evidenced by the reduced amounts of [3-(13)C]alanine and [3-(13)C]lactate. Additionally, neuronal oxidative metabolism of [1-(13)C]glucose was decreased in ketotic rats compared with controls, since amounts of [4-(13)C]glutamate and [4-(13)C]glutamine were lower than those of controls. Although the amount of glutamate from [1-(13)C]glucose was decreased, this was not the case for GABA, indicating that relatively more [4-(13)C]glutamate is converted to GABA. Astrocytic metabolism was increased in response to ketosis, shown by increased amounts of [4,5-(13)C]glutamine, [4,5-(13)C]glutamate, [1,2-(13)C]GABA and [3,4-(13)C]-/[1,2-(13)C]aspartate derived from [1,2-(13)C]acetate. The pyruvate carboxylation over dehydrogenation ratio for glutamine was increased in the ketotic animals compared to controls, giving further indication of increased astrocytic metabolism. Interestingly, pyruvate recycling was higher in glutamine than in glutamate in both groups of animals. An increase in this pathway was detected in glutamate in response to ketosis. The decreased glycolysis and oxidative metabolism of glucose as well as the increased astrocytic metabolism, may reflect adaptation of the brain to ketone bodies as major source of fuel.     

Endothelial and vascular dysfunctions and insulin resistance in rats fed a high-fat, high-sucrose diet

This study was designed to examine the effects of a high-fat, high-sucrose (HFHS) diet on vascular and metabolic actions of insulin. Male rats were randomized to receive an HFHS or regular chow diet for 4 wk. In a first series of experiments, the rats had pulsed Doppler flow probes and intravascular catheters implanted to measure blood pressure, heart rate, and regional blood flows. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine skeletal muscle glucose transport activity and to determine in vitro vascular reactivity, endothelial nitric oxide synthase (eNOS) protein expression in muscle and vascular tissues and endothelin content, nitrotyrosine formation, and NAD(P)H oxidase protein expression in vascular tissues. The HFHS-fed rats displayed insulin resistance, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, elevated blood pressure, and impaired insulin-mediated renal and skeletal muscle vasodilator responses. A reduction in endothelium-dependent vasorelaxation, accompanied by a decreased eNOS protein expression in muscles and blood vessel endothelium, and increased vascular endothelin-1 protein content were also noted in HFHS-fed rats compared with control rats. Furthermore, the HFHS diet induced a reduced insulin-stimulated glucose transport activity in muscles and increased levels of NAD(P)H oxidase protein and nitrotyrosine formation in vascular tissues. These findings support the importance of eNOS protein in linking metabolic and vascular disease and indicate the ability of a Westernized diet to induce endothelial dysfunction and to alter metabolic and vascular homeostasis.     

Hypocholesterolemic effects of phenolic-rich extracts of Chemlali olive cultivar in rats fed a cholesterol-rich diet

This study was designed to test the lipid-lowering and the antioxidative activities of green and black olive phenolic extracts. Wistar rats fed a standard laboratory diet or a cholesterol-rich diet for 16 weeks were used. The serum lipid levels, the malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) as well as that of catalase (CAT) were examined. The cholesterol-rich diet induced hypercholesterolemia that was manifested in the elevation of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). Administration of aqueous methanol and ethyl acetate extracts of green olives and ethyl acetate extract of black olives significantly lowered the serum levels of TC and LDL-C, while increasing the serum level of high density lipoprotein cholesterol (HDL-C). Furthermore, the content of MDA in liver, heart and kidney decreased significantly after oral administration of green and black olive extracts compared with those of rats fed a cholesterol-rich diet. In addition, olive extracts increased CAT and SOD activities in liver. These results suggested that the hypocholesterolemic effect of green and black olive extracts might be due to their abilities to lower serum cholesterol level as well as to slow down the lipid peroxidation process and to enhance the antioxidant enzyme activity.     

Cell division in kidneys of rats fed a potassium-deficient diet

Mitoses is stimulated in the kidneys of adult rats fed a potassium-deficient diet. A statistically significant increase in mitotic figures appears first in the collecting ducts of the inner strip of the outer medulla after two days on the K+ deficient diet (P less than 0.05). After six days, mitosis also increases in the collecting ducts in the outer stripe and in the inner medulla (P less than 0.01). After eight days there is a significant rise in mitotic activity in the cells of the proximal convoluted tubule (P less than 0.01). There is a questionable increase in mitosis found only on the fifth day in the distal convoluted tubule. In all other cell types there is no statistically significant increase in cell division over the normal low levels that are observed in the cells of the controls rats.     

"In vitro" effects of insulin on the PDH complex of the isolated perfused heart of rats fed a sucrose-rich diet.

We have recently reported that the "in situ" myocardial concentrations of the active form of the Pyruvate Dehydrogenase Complex (PDHa) were significantly decreased in hearts obtained from normal rats fed for 3 weeks on an isocaloric sucrose rich (63%) diet (SRD) when compared to age matched controls fed on the standard laboratory chow (STD). Since, on the one hand SRD rats present glucose intolerance and impaired "in vivo" insulin action and, on the other hand the effects of insulin on the interconversion of heart PDH remains a controversial matter, we found it relevant to study the effects of insulin on the PDH complex in the "in vitro" perfused (Langendorff technique) heart preparations obtained from SRD rats. After a 35 minute perfusion period with 5.5 mM glucose as the only nutrient in the perfusate, PDHa as a percentage of total PDH was found to remain significantly lower in SRD hearts (M +/- SEM 32.6 +/- 2.3) when compared to STD hearts (68.3 +/- 4.6, P less than 0.05) in spite of comparable total PDH activities in both groups of animals. Although the addition of insulin to the perfusate (20 mu/ml) resulted in a significant increase in the percentage of PDHa (45.8 +/- 3.4) of SRD heart, values attained still remained significantly lower than those obtained in STD controls (67.5 +/- 3.6; P less than 0.05). Simultaneously, the addition of insulin to the perfusate, significantly reduced the Acetyl-CoA/CoASH ratio in SRD hearts although this ratio remained still much higher than those observed in STD controls under the same experimental conditions.     

Antioxidative and antihypertensive effects of Welsh onion on rats fed with a high-fat high-sucrose diet

The effects of Welsh onion on the development of hypertension and autoxidation were studied in 6-week-old male Sprague-Dawley rats. The rats were fed with a control diet or a high-fat high-sucrose (HFS) diet with or without 5% Welsh onion (green-leafy type or white-sheath type) for 4 weeks. The systolic blood pressure was elevated and the thiobarbituric acid reactive substances (TBARS) in plasma were increased in the rats fed with the HFS diet without Welsh onion. The rats fed with the HFS diet containing Welsh onion, especially the green-leafy type, had lower blood pressure. They also had a higher level of nitric oxide (NO) metabolites in both the urine and plasma, lower activity of NADH/NADPH oxidase in the aorta, and suppressed angiotensin II production. The effect of white Welsh onion on decreasing the blood pressure was not significant, although the effects on increasing NO metabolites in the urine and decreasing NADH oxidase activity in the aorta were significant. The TBARS value in the plasma was lowered in the rats fed with either green or white Welsh onion, but the in vitro radical scavenging and ferric reducing antioxidative activities were much higher with green Welsh onion than with the white type. These results suggest that the green-leafy Welsh onion, but not the white type, reduced superoxide generation by suppressing the angiotensine II production and then the NADH/NADPH oxidase activity, increasing the NO availability in the aorta, and consequently lowering the blood pressure in the rats fed with the HFS diet. The radical scavenging and reducing antioxidative activities of green Welsh onion may also be effective in decreasing superoxide.     

Maternal green tea extract supplementation to rats fed a high-fat diet ameliorates insulin resistance in adult male offspring

Maternal overnutrition is associated with increased risk of metabolic disorders in the offspring. This study tested the hypothesis that maternal green tea (GT) supplementation can alleviate metabolic derangements in high-fat-diet-fed rats born of obese dams. Female Sprague–Dawley rats were fed low-fat (LF, 7%), high-fat (HF, 30%) or HF diet containing 0.75% or 1.0% GT extract (GT1, GT2) prior to conception and throughout gestation and lactation. Both doses of GT significantly improved metabolic parameters of HF-fed lactating dams (P<.05). Birth weight and litter size of offspring from HF dams were similar, but GT supplementation led to lighter pups on day 21 (P<.05). The weaned male pups received HF, GT1 or GT2 diet (dam/pup diet groups: LF/HF, HF/HF, HF/GT1, HF/GT2, GT1/HF and GT2/HF). At week 13, they had similar weight but insulin resistance index (IRI), serum nonesterified fatty acid (NEFA) and liver triglyceride of rats born to GT dams were 57%, 23% and 26% lower, accompanied by improved gene/protein expressions related to lipid and glucose metabolism, compared with the HF/HF rats (P<.05). Although HF/GT1 and HF/GT2 rats had lower serum NEFA, their insulin and IRI were comparable to HF/HF rats. This study shows that metabolic derangements induced by an overnourished mother could be offset by supplementing GT to the maternal diet and that this approach is more effective than giving GT to offspring since weaning. Hence, adverse effects of developmental programming are reversible, at least in part, by supplementing bioactive food component(s) to the mother's diet.     

Plasma glucose and insulin responses in growing rats fed a total parenteral nutrition diet either intravenously or intragastrically

The effect of administering either intravenously (group I) or intragastrically (group II) a glucose-amino acid total parenteral nutrition diet over a 12-day period upon plasma glucose and insulin responses was examined in adolescent rats. Infusion of the 25% glucose - 12.2% amino acid diet at a rate of 300 kCal X kg body weight-1 X 24 h-1 supported normal weight gain over the 12-day study period in both intravenously (group I) and intragastrically (group II) alimented rats. Mean plasma glucose levels rose dramatically in both groups by the end of day 1; group I had significantly higher mean plasma insulin levels. By day 3, the group I mean plasma glucose value decreased significantly while the group II mean glucose value remained virtually unchanged. Mean plasma insulin values more than doubled in both groups with the group I level still remaining significantly above the group II level. At days 6 and 12, group I mean plasma glucose levels were significantly below group II while both groups had similar plasma insulin levels. Data from this 12-day intravenous-intragastric alimentation study reveals quite different metabolic responses compared with acute (120-180 min) studies of the enteroinsular axis.     

Intraventricular insulin potentiates the anorexic effect of corticotropin releasing hormone in rats

Intraventricular corticotropin releasing hormone (CRH) suppresses food intake and body weight as a stress response. Insulin, acting within the brain, also suppresses food intake and body weight, and this suppression is related to caloric homeostasis. We determined if increased insulin within the brain potentiates the anorexic effects of intraventricular CRH. Rats were food deprived for 17 h each day and then given 30-min access to Ensure. One-half received continuous third ventricular infusion of synthetic cerebrospinal fluid via osmotic minipumps, and one-half received insulin (0.6 mU/day). During the infusion, rats also received 0, 0.1, 1.0, or 5.0 microg of CRH into the lateral ventricle just before access to Ensure. Insulin alone had no effect on Ensure intake or body weight. CRH dose dependently reduced Ensure intake in both groups, and the reduction was greater in the insulin group. Hence, central insulin potentiated the ability of centrally administered CRH to suppress food intake. These findings suggest that stress-related influences over food intake, particularly those mediated via CRH, interact with relative adiposity as signaled to the brain by central insulin.     

Changes in expression of skeletal muscle proteins between obesity-prone and obesity-resistant rats induced by a high-fat diet

A primary goal in obesity research is to determine why some people become obese (obesity-prone, OP) and others do not (obesity-resistant, OR) when exposed to high-calorie diets. The metabolic changes that cause reduced adiposity and resistance to obesity development have yet to be determined. We thus performed proteomic analysis on muscular proteins from OP and OR rats in order to determine whether other novel molecules are involved in this response. To this end, rats were fed a low- or high-fat diet for 8 weeks and were then classified into OP and OR rats by body weight gain. OP rats gained about 25% more body weight than OR rats, even though food intake did not differ significantly between the two groups. Proteomic analysis using 2-DE demonstrated differential expression of 26 spots from a total of 658 matched spots, of which 23 spots were identified as skeletal muscle proteins altered between OP and OR rats by peptide mass fingerprinting. Muscle proteome data enabled us to draw the conclusion that enhanced regulation of proteins involved in lipid metabolism and muscle contraction, as well as increased expression of marker proteins for oxidative muscle type (type I), contributed to obesity-resistance; however, antioxidative proteins did not.