Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist

Neuropeptide Y has been proposed to play a major role in the hypothalamic regulation of feeding behavior through the activation of specific, central NPY receptor(s). In an effort to design small molecule antagonists of NPY receptors, we have synthesized a series of substituted dipeptides based on defined pharmacophores, previously identified by us and others as essential for the interaction with the peptide receptors. GI264879A behaves as a functional antagonist of Y1 receptors while displaying no binding selectivity for the different NPY receptor subtypes. We demonstrate here that administration of GI264879A to rats causes a significant decrease in food intake and body weight partly through a mechanism dependent on the integrity of the vagus nerve.     

Suppression of food intake and body weight gain by naloxone in rats

The effect of acute and chronic administration of naloxone on food acquisition and weight gain in rats was studied in 3 experiments. One injection of a sparingly-soluble salt of naloxone in slow-release vehicle markedly lowered mean food intake over that of control rats injected with the vehicle only. Mean body weight of the naloxone-injected rats was significantly lower than that of the control group for one week.Repeated evening injections (2000 h) of naloxone hydrochloride in saline tended to reduce the night-time feeding below control levels throughout the 10-day period of naloxone administration. Food intake was significantly lower in the 4- and 8-h periods after the first injection of naloxone than that on the preceding saline control night. The initial decreases were offset by increased day-time feeding so that total daily food intake was not significantly altered over the 10 days. When saline was substituted for naloxone, food intake increased.Rats given naloxone following 24 h of fasting consumed significantly less food and gained less weight during 4 h of access to food compared to those receiving saline. After a 48-h fast naloxone-treated rats also gained significantly less body weight than those given saline, but the reduction in food intake was not statistically significant. These results suggest the possibility that endorphins may have a modulating effect on feeding activity.     

Food intake of suckling rats after administration of glucose and amino acids

The changes of food intake after administration of glucose or a mixture of amino acids were determined in rat pups from the 5th to the 23rd day of life. The milk intake was significantly reduced 90 min after glucose treatment in 17 day-old pups, while decreased food intake after injection of aminoacids was observed only after the 23rd day of life. It is being concluded that the regulation of food intake in correlation to the blood concentrations of various key metabolic factors develops gradually during the suckling period, depending on the development of the CNS and on changes in diet composition.     

The effect of insulin deficiency, dietary protein intake, and plasma amino acid concentrations on brain amino acid levels in rats

The effect of diabetes (streptozotocin, 65 mg/kg ip), dietary protein intake (15-60%), and plasma amino acid concentrations on brain large neutral amino acid levels in rats was examined. After 20 days, the plasma concentrations of methionine and the branched chain amino acids (BCAA), valine, isoleucine, and leucine were increased in diabetic rats. In brain tissue, methionine and valine levels were increased but threonine, tyrosine, and tryptophan concentrations were depressed. Increased protein consumption promoted a diabetic-like plasma amino acid pattern in normal rats while enhancing that of diabetic animals. However, with the exception of threonine, glycine, valine, and tyrosine, there was little effect on brain amino acid levels. A good association was found between the calculated brain influx rate and the actual brain concentration of threonine, methionine, tyrosine, and tryptophan in diabetic animals. There was no correlation, however, between brain influx rate and brain BCAA levels. Thus, the brain amino acid pattern in diabetes represents the combined effects of insulin insufficiency and composition of the diet ingested on plasma amino acid levels as well as metabolic adaptation within the brain itself.     

The effect of acarbose on the food intake, weight gain, and adiposity of LA/N-cp rats.

1. Groups of lean and obese LA/N-cp rats were administered the intestinal glucosidase inhibitor acarbose at 150 or 300 mg/kg diet from 7 until 17 weeks of age and the effects of the drug on food intake patterns and adiposity determined. 2. Dose related effects on body weights, adiposity and feed efficiency ratio were observed (control greater than 150 mg greater than 300 mg drug/kg diet) following treatment in both phenotypes, with the greatest differences observed in the obese phenotype. 3. Acarbose at both dosages was associated with phenotype-specific alterations in food intake amount and feeding pattern, resulting in an attenuation of age-associated increases in food intake. The feed efficiency ratio decreased in both phenotypes, and approached normally fed lean controls in obese rats administered the greater dosage. 4. These results indicate that patterns of food intake and weight gain differ markedly between lean and obese rats of this strain, and acarbose brings about a dose-related attenuation of developing food intake patterns in both phenotypes and which are associated with decreases in weight gain and adiposity. Thus, this drug may have therapeutic potential as an adjunct agent in the treatment of obesity and/or other disorders of carbohydrate intolerance.     

Food intake and mass gain of hand-reared brown bear cubs

Five orphaned European brown bear cubs (Ursus arctos) from 3 litters were hand-reared from the ages of 1–4 months. Body mass initially ranged from 1.7 to 2.8 kg. Growth rates were monitored with reference to diet. Over a period of 3 years, 6 different feed formulas were used. The first 4 formulas were given with bottles until an average age of 133 days. Conversion to mass in the first 10 months ranged from 3.5 to 32.0 g of food per gram of body mass (or 38.1–192.6 kJ of gross energy/gram body mass), and was affected by type of diet. High fat content increased, whereas high carbohydrate content decreased the conversion rates. Formula 3, with 12.0% protein, 23.9% fat, and only 0.2% carbohydrates, simulated values found in bears' milk and produced the best growth rates. Formula 6 (bread, fruits, and meat) was used from ages 7 to 35 months, and over this period, the efficiency of gross energy conversion decreased gradually, by an eventual factor of 3.8. Hand-reared cubs ranged from 1.3 to 2.7 times heavier than 17 wild cubs measured at matching ages. Wild mass is probably limited by maternal hibernation, and by the largely herbivorous nature of the diet. © 1993 Wiley-Liss, Inc.     

Captopril intake decreases body weight gain via angiotensin-(1-7)

Angiotensin-(1-7) [Ang-(1-7)] plays a beneficial role in cardiovascular physiology by providing a counterbalance to the function of angiotensin II (Ang II). Although Ang II has been shown to be an adipokine secreted by adipocyte and affect lipid metabolism, the role of Ang-(1-7) in adipose tissue remains to be clarified. The aim of the present study was to investigate whether Ang-(1-7) affects lipid metabolism in adipose tissue. Ang-(1-7) increased glycerol release from primary adipocytes in a dose-dependent manner. A lipolytic effect of Ang-(1-7) was attenuated by pretreatment with A-779, a Mas receptor blocker and with an inhibitor of phosphoinositol 3-kinase (PI3K), or eNOS. However, losartan and PD123319 did not cause any change in Ang-(1-7)-induced lipolysis. Ang-(1-7)-induced lipolysis had an addictive effect with isoproterenol. In normal rats, chronic intake of captopril for 4 wks decreased body weight gain and the amount of adipose tissue and increased plasma Ang-(1-7) level. These effects were attenuated by administration of A-779. The levels of Mas receptor and phosphorylation of hormone-sensitive lipase (p-HSL) were significantly increased by treatment with captopril and these captopril-mediated effects were attenuated by the administration of A-779. There was no difference in diameter of adipocytes among sham, captopril- and captopril+A-779-treated groups. The similar effects of captopril on body weight, expression of Mas receptor, and p-HSL were observed in Ang-(1-7)-treated rats. These results suggest that captopril intake decreased body weight gain partly through Ang-(1-7)/Mas receptor/PI3K pathway.     

Inhibition of apple 1-aminocyclopropane-1-carboxylic acid oxidase, by cyclopropane-1,1-dicarboxylic acid and trans-2-phenylcyclopropane-1-carboxylic acid

Cyclopropane-1,1-dicarboxylic acid (CDA) and trans-2-phenylcyclopropane-1-carboxylic acid (PCCA) are the main representatives of a group of compounds that are structural analogues of 1-aminocyclopropane-1-carboxylic acid (ACC) and have been proved to have an inhibitory effect on the wound ethylene produced by Lycopersicum esculentum fruit discs. During the experiments, that were carried out in this work the inhibition pattern of PCCA and CDA were studied when tested on partially purified apple ACO and their Ki values were determined. A mechanistic proposal was given, in order to explain the kinetic behaviour of the inhibitors. The common feature of these molecules is their cyclopropane ring, with different substitutes mainly at the positions C1 and C2. Two other compounds with similar structure where also tested as inhibitors, in order to clarify the relationship between structure and activity. These compounds are: 2-methyl cyclopropanecarboxylic acid (MCA), and cyclopropanecarboxylic acid (CCA).     

Effect of serum estradiol and leptin levels on thyroid function, food intake and body weight gain in female Wistar rats

We evaluated the interplay among estrogen, leptin and thyroid function in the regulation of body mass in female rats. Adult female rats were divided into four groups: control (C, sham-operated), ovariectomized (OVX), ovariectomized treated with estradiol benzoate (Eb) 0.7 or 14 μg/100 g bw per day, during 21 days. OVX led to an increase in body mass, food intake and food efficiency (change in body mass as function of the amount of food ingested) which were normalized by the lower Eb dose, and decreased significantly when the higher dose was given. Serum leptin levels were increased more than two-fold in all ovariectomized groups. Serum T4 levels of the Eb treated OVX were significantly lower than in the controls. Serum T3 and TSH were unaffected by OVX or by Eb treatment. Uterine type 2 iodothyronine deiodinase (D2) activity changed in parallel with serum estradiol: decreased after OVX, returned to control levels after the lower E2 treatment, and increased significantly after the high Eb dosage. The hypothalamic D2 activity was reduced around 30% in all castrated groups, treated or not with estrogen, whereas in the brown adipose tissue the enzyme was not changed. Interestingly, although estrogen-treated OVX rats had lower body weight, serum leptin was high, suggesting that estrogen increases leptin secretion. Our results show that estradiol is necessary for the hypothalamic action of leptin, since the increase in leptin levels observed in all ovariectomized rats was associated with a decrease in food intake and food efficiency only in the rats treated with estrogen.     

Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.     

Essential amino acid supplements increase muscle weight, bone mass and bone strength in adult osteoporotic rats

Protein undernutrition is known to play an important role in the pathogenesis of osteoporotic fracture in elderly. The mechanisms underlying the bone loss in protein undernutrition appeared to be related to an uncoupling between increased bone resorption and bone formation. This was associated with decreased plasma IGF-I levels, with anoestrus and decreased muscle mass. Reversibility of protein undernutrition-induced bone loss was investigated in ovariectomized adult rats, which were fed isocaloric 2.5 % casein diet (OVX2.5) for 16 weeks. Then, the animals were given a supplement of essential amino-acids in similar proportion to that of casein at doses of 2.5% (EAA2.5) or 5% (EAA5) of total food intake for an additional 16 weeks. Essential amino acid supplements increased bone mineral mass and strength in ovariectomized protein-deprived rats. EAA supplements were associated with stimulated bone formation and reduced bone resorption, with increment of plasma IGF-I and of limb muscle mass weight. These results suggest that nutritional intervention with essential amino acid supplements can increase bone mineral mass, bone strength and muscle mass in osteoporotic rats possibly by correcting IGFI status.