Biomedical subjects

D A York

Publications and source records attributed to D A York.

At least 73 records · Page 4Linked to original sources

PubMed1994

Structural requirements for the biological activity of enterostatin.

A series of enterostatin analogues were tested to investigate the minimal structure required for activity to suppress the intake of high-fat (HF) diets. The dose-response curve to intracerebroventricular (ICV) enterostatin was U-shaped (maximal inhibition at 1 nmol). Removal or modification of the N-terminal valine from enterostatin (Val-Pro-Asp-Pro-Arg) abolished activity, as did C-terminal amidation. The tripeptide (Pro-Asp-Pro) and the cyclo-diketopiperazine cyclo-Asp-Pro retained activity whereas the linear Asp-Pro dipeptide was inactive. In rats adapted to a three-choice macronutrient diet, cyclo-Asp-Pro specifically inhibited fat intake and had near maximal inhibition (50%) at the 0.03 nmol dose. The enterostatin inhibitory effect on fat intake may reside in the cyclo-diketopiperazine molecule, cyclo-Asp-Pro.

Amino Acid Sequence↗

PubMed1994

Chronic cerebroventricular galanin does not induce sustained hyperphagia or obesity.

Acute central administration of galanin has been reported to increase fat consumption. These experiments were designed to test the hypothesis that repeated injections of galanin would elicit hyperphagia and weight gain and that this response would depend on the available diet. Male Sprague-Dawley rats were fed high (56% energy) or low (10% energy) fat diets. Galanin (300 pmol) or saline vehicle was injected into the third ventricle twice daily for 7 days and three times daily for another 6 days. On both the high-carbohydrate and high-fat diets, twice daily galanin increased daytime food intake, but there was a compensatory decrease in nighttime intake. The addition of a third, nighttime injection of galanin was ineffective in producing an increase in total 24-h intake. There was no significant increase in body weight during galanin treatment in rats eating either diet although animals eating the high-fat diet gained more weight as reflected by a significant increase in epididymal fat pad weight. Galanin treatment had no effects on serum insulin, glucose or corticosterone concentrations, measured at the end of the experiment. However, animals fed the high-fat diet had significantly higher insulin concentrations at the time of sacrifice. Although repeated central infusions of galanin reliably stimulated daytime intake of both diets, they failed to increase total daily energy intake or body weight.

Animals↗

PubMed1994

Relationship between food intake and metabolic rate in rats treated with beta-adrenoceptor agonists.

The purpose of the present experiment was to clarify the interaction between food intake and activity of the thermogenic component of the sympathetic nervous system by studying the dose response relationships of typical beta 1-, beta 2-, and beta 3-adrenoceptor agonists on oxygen consumption and food intake. The data showed that the ED50 for the effects of Dobutamine (beta 1), Clenbuterol (beta 2) and ICI D7114 (beta 3) agonists on food intake were 8.9, 0.041 and > 1.1 mumol/kg respectively whereas the ED50 values for stimulation of metabolic rate were 7.1, 1.3 and 0.11 mumole/kg respectively. The marked differences in ED50 values for suppression of food intake and stimulation of metabolic rate for both clenbuterol and ICI D7114 suggest that the regulation of feeding and of metabolic rate in response to these agonists are independent of each other. The experiments also identified that Clenbuterol activated a very sensitive beta 2-adrenergic system for the regulation of feeding behavior.

Adrenergic beta-Agonists↗

PubMed1993

Procolipase mRNA: tissue localization and effects of diet and adrenalectomy.

Northern blot analysis has identified procolipase mRNA in rat pancreas, stomach and duodenum. Pancreatic colipase mRNA was increased by high-fat diets. Adrenalectomy increased pancreatic procolipase mRNA, an effect enhanced by high-fat diets. The results suggest that colipase is not unique to the pancreas and that diet and glucocorticoids interact in regulating the transcription of its gene.

Actins↗

PubMed1993

Effects of the glucocorticoid agonist, RU28362, and the antagonist RU486 on lung phosphatidylcholine and antioxidant enzyme development in the genetically obese Zucker rat.

The biochemical maturation of the lung in late gestation and in the young animal is regulated by glucocorticoids. The present study was aimed at dissociating the different glucocorticoid receptor sites involved in these regulatory functions. The obese Zucker rat was selected as a model for this study as it exhibits hypersensitivity to glucocorticoid hormone action by virtue of its elevated receptor numbers and activity. Two synthetic steroid analogues were administered to obese animals; RU28362, a specific type II receptor agonist, and the type II antagonist RU486. RU28362 promoted a strong catabolic effect, which was associated with reduced food intake and the abolition of growth in the rats. The agonist, RU28362, attenuated developmental increases in antioxidant enzyme activities, and altered the growth of the tissue. At the age studied, development of the lung phosphatidylcholine (PC) system was almost complete, but RU28362 increased disaturated PC 16:0/16:0 concentrations by almost 2-fold, and altered the molecular composition of total pulmonary PC. RU486 attenuated the growth of the rats and reduced their food intake. Treatment with the type II antagonist attenuated lung growth and increased the activities of pulmonary copper zinc (Cu/Zn) and manganese (Mn) superoxide dismutases. RU486 had no effect on lung PC concentrations and molecular composition. The data suggest a role for type I glucocorticoid receptors in the regulation of the antioxidant enzyme system in the lung, as type II antagonism will channel endogenous glucocorticoid binding to the type I site. Type II receptor binding would appear to play a role in regulating the lung PC content.

Androstanols↗

PubMed1993

Effect of enterostatin on the feeding responses to galanin and NPY.

We have investigated the possibility that enterostatin may inhibit the intake of dietary fat by inhibiting either galanin or NPY-induced feeding pathways. Rats, adapted to either high fat (HF) or low fat-high carbohydrate (HC) diets and fitted with third ventricular cannulas were used to study the effects of intracerebroventricular (i.c.v.) enterostatin on i.c.v. NPY and galanin induced feeding responses in satiated rats. An equimolar dose of enterostatin (0.1 nmoles) inhibited, while a tenfold excess of enterostatin abolished the feeding response to galanin in rats adapted to a HF diet. The galanin stimulation of food intake was reduced in rats adapted to the HC diet and this response was less sensitive to inhibition by enterostatin. Enterostatin had no inhibitory effects on NPY-induced feeding in rats adapted to the HC diet and only a small inhibitory effect, at tenfold molar excess, in rats adapted to the HF diet. The ability of enterostatin to bind to galanin or NPY Y-1 receptors was investigated in ligand binding studies. Enterostatin failed to displace 125I-galanin or 125I-PYY from specific binding sites in rat forebrain homogenates or SK-N-MC cells respectively. The data provide support for the hypothesis that enterostatin specifically inhibits a galanin-responsive fat intake system, but indicate that this effect is not modulated by direct interaction with either galanin or NPY-Y1 receptors.

Analysis of Variance↗

PubMed1993

Chronic effects of intracerebral ventricular enterostatin in Osborne-Mendel rats fed a high-fat diet.

Enterostatin, a pentapeptide found in the procolipase molecule of the pancreas, has been infused chronically into the lateral ventricle of Osborne-Mendel rats for 11 days. Treatment with enterostatin acutely lowered food intake more in the treated animals than in the vehicle-treated controls. Weight gain and serum insulin were significantly reduced by enterostatin. Corticosterone was significantly increased in rats receiving chronic infusions of enterostatin into the lateral ventricle and was also increased following an acute ICV injection of enterostatin. CRH antagonist did not block the acute feeding response to enterostatin in Sprague-Dawley rats. The elevation of corticosterone during chronic infusion of enterostatin reduced the level of hepatic glucocorticoid receptor as measured by Western blot. We conclude that body weight gain of OM rats is reduced by centrally administered enterostatin, and that the acute effects of enterostatin on food intake are not mediated through stimulation of CRH secretion.

Animals↗

PubMed1993

The peptide enterostatin may produce early satiety.

The time course of feeding, grooming, exploration, and sleeping behaviors has been measured following treatment with enterostatin, the signal pentapeptide from procolipase. The peptide was injected intraperitoneally prior to presenting food, and the frequency of feeding and grooming activity, drinking, and rest or sleeping were observed at 10-s intervals for 60 min. Enterostatin did not delay the onset of feeding but shortened the time spent eating compared to saline injected controls. Conversely, grooming activity appeared earlier following enterostatin, activity was reduced, and resting behavior occurred earlier with this peptide. There were no changes in the drinking behavior. For the first hour following enterostatin, eating represented 20.8% of the time, grooming 9.2%, activity 18.3%, and rest or sleep 47.2%, with drinking making up the other 4.4%. In contrast, saline-injected animals ate for 27.1% of the time, groomed for 12.4%, were active 28.5% of the time, had sleep or rest time equal to 27.9%, and drank for 4.1% of the time. In fasted animals, the onset of grooming, the decrease in activity, and the increase in time sleeping occurred earlier than with saline. These studies support the concept that enterostatin decreases food intake by producing early satiety.

Animals↗

PubMed1993

d-fenfluramine in a rat model of dietary fat-induced obesity.

d-Fenfluramine is an appetite suppressant drug that acts by releasing serotonin from axon terminals and inhibiting its reuptake. S 5B/P1 rats, which are resistant to dietary-fat induced obesity, and Osborne-Mendel rats, which are sensitive, were adapted to ad lib feeding of either a low- or high-fat diet. d-Fenfluramine (10 mg/kg, IP) was injected daily for 12 days. Other than a slightly greater suppression of food intake in Osborne-Mendel rats, there was little difference in response to d-fenfluramine between S 5B/P1 and Osborne-Mendel rats eating the low-fat diet. However, in Osborne-Mendel rats d-fenfluramine completely abolished the excess food intake and weight gain associated with the high-fat diet. Purine nucleotide (GDP) binding on day 13 was higher in S 5B/P1 rats than in Osborne-Mendel rats and was increased by d-fenfluramine in animals of both strains eating the low-fat diet. The high-fat diet increased GDP binding only in S 5B/P1 rats and blocked the fenfluramine-induced increase in GDP binding in both strains. We speculate that d-fenfluramine blocks a feeding reward system stimulated by the high-fat diet.

Animals↗

PubMed1993

Adrenalectomy of the obese Zucker rat: effects on the feeding response to enterostatin and specific mRNA levels.

The effects of adrenalectomy on the feeding response to enterostatin and the mRNA levels of its parent protein, pancreatic colipase, have been investigated in lean (fa/?) and genetically obese (fa/fa) rats. Adrenalectomy reduced body weight gain and food intake of obese rats. Enterostatin inhibited the intake of high-fat diet in obese rats but not in lean rats. Adrenalectomy reduced food intake of all rats and abolished the response to enterostatin in the obese group. Obese rats had low levels of colipase mRNA, but these were normalized after adrenalectomy. The ability to respond to exogenous enterostatin is possibly linked to low levels of production of the peptide. The effects of adrenalectomy on brown adipose tissue uncoupling protein (UCP) mRNA and beta 3-adrenergic receptor (beta 3-AR) mRNA were also investigated. Northern blot analysis showed low levels of both UCP mRNA and beta 3-AR mRNA in obese rats that were restored to or toward the normal levels of lean rats by adrenalectomy. Adrenalectomy had no significant effects on mRNA levels in lean rats.

Adipose Tissue, Brown↗

PubMed1992

Mifepristone (RU 486), a blocker of type II glucocorticoid and progestin receptors, reverses a dietary form of obesity.

The effect of mifepristone (RU 486), a blocker of type II glucocorticoid receptors on the development of obesity that follows the feeding of a high-fat (HF) diet to Osborne-Mendel (OM) rats, has been investigated. OM rats fed a HF diet gained more weight and had larger retroperitoneal and parametrial fat pads than OM rats fed a high-carbohydrate low-fat (LF) diet. RU 486 (30 mg.kg-1.day-1) for 14 days completely reversed the body weight gain and the increase in fat pad size of OM rats fed a HF diet. RU 486 had no effect on body weight of OM rats fed a LF diet, but did reduce fat pad weights. The data suggest that type II glucocorticoid receptor activity modulates body fat deposition and is essential for the development of obesity, although a minor role for progestin receptor activity cannot be ruled out.

Animals↗

PubMed1992

Differential inhibition of fat intake in two strains of rat by the peptide enterostatin.

The effect of enterostatin, the amino-terminal pentapeptide of pancreatic procolipase, on food intake was investigated in two strains of rat, the dietary fat-sensitive Osborne-Mendel (OM) rat and the dietary fat-resistant S5B/Pl rat. After an overnight fast, enterostatin inhibited intake of high-fat (HF) but not low-fat (LF) diets in OM rats, but had no effect in S5B/Pl rats. When fed a macronutrient three-choice diet, OM rats selected fat preferentially, whereas S5B/Pl rats selected carbohydrate. Enterostatin specifically inhibited the intake of fat in OM rats but not S5B/Pl rats fed a three-choice macronutrient diet. The activity of pancreatic colipase was increased in S5B/Pl rats on both HF and LF diets compared with OM rats. Pancreatic colipase activities were negatively related to the voluntary intake of fat on three-choice macronutrient diets. The data support the hypothesis that enterostatin may control the intake of dietary fat.

Animals↗

PubMed1992

Glucocorticoid receptor numbers in the brain and liver of the obese Zucker rat.

Scatchard analysis of ligand binding activity has been used to investigate type I and type II glucocorticoid receptor subtypes in the hippocampus, hypothalamus and liver of lean and genetically obese fa/fa rats. Despite normal levels of corticosterone in the hypothalamus and hippocampus of fa/fa rats, maximum binding to both type I and type II receptors was increased in the hippocampus and hypothalamus. The KD value of type I receptors was normal in fa/fa rats (lean 0.13 nM, obese 0.15 nM) whereas the KD for corticosterone binding to type II receptors was increased (lean 0.48nM, obese 1.02nM). Adrenalectomy increased Bmax of type II receptors in lean rats in a time dependent manner but had no effect on binding to receptors of obese rats after the initial clearance of endogenous bound ligand. KD values were not altered by adrenalectomy in either genotype. There were no differences in binding of corticosterone to hepatic receptors of lean and obese rats seven days after adrenalectomy. The data suggests that glucocorticoid binding to type I and type II receptors is abnormally regulated in the brains of fa/fa rats.

Animals↗

PubMed1991

Enterostatin (Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake.

Valine-proline-aspartate-proline-arginine (VPDPR), the amino terminal pentapeptide of pancreatic procolipase, produced a dose-dependent reduction in food intake when injected intraperitoneally into Osborne-Mendel rats that had been starved overnight. This inhibition of feeding was observed when the rats were fed a high-fat diet but not in rats fed a high-carbohydrate, low-fat diet. At higher doses of VPDPR, the inhibition of feeding was maintained for over 6 hours. An equimolar mixture of the free amino acids had no effect on food intake. In rats adapted to a three-choice macronutrient diet, VPDPR inhibited fat intake but had no effect on carbohydrate or protein intake. This selective inhibition of fat intake was observed in both overnight-fasted rats presented with food and in ad-lib-fed rats at the beginning of the dark-onset feeding period. It is suggested that this peptide may be a feedback signal to regulate the intake of dietary fat.

Animals↗

PubMed1991

Adrenalectomy in the Zucker fatty rat: effect on m-RNA for malic enzyme and glyceraldehyde 3-phosphate dehydrogenase.

The effects of adrenalectomy with or without replacement doses of corticosterone were examined on the levels of messenger RNA for malic enzyme (ME) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in adipose tissue and liver from Zucker fatty (fa/fa) and littermate lean rats. The levels of both GAPDH and ME mRNAs were increased in the obese rats. Adrenalectomy markedly reduced the m-RNA for GAPDH and ME in Zucker fatty rats to the low levels observed in adrenalectomized lean rats. Corticosterone treatment induced a greater and earlier increase in mRNA levels in adrenalectomized obese rats than in adrenalectomized lean rats. Since the fatty rat represents an autosomal recessive trait, these results are consistent with the hypothesis that the genetic defect is a loss of a modulator of steroid action which normally restricts the response of genes to glucorticoid hormones.

Adipose Tissue↗

PubMed1991

Central glucocorticoid regulation of parasympathetic drive to pancreatic B-cells in the obese fa/fa rat.

The effects of glucocorticoids on the insulin secretory response to an intravenous glucose load have been studied in lean (Fa/?) and obese fa/fa Zucker rats. The role of parasympathetic drive to the pancreatic B-cells was assessed as that component of the insulin secretory response that was blocked by pretreatment of the rats with intravenous atropine. The insulin secretory response to the glucose load was greater in obese than in lean rats. Atropine significantly reduced basal and stimulated levels of insulin in obese but not in lean rats. Adrenalectomy reduced basal insulin levels and the secretory response in obese but not lean rats and also abolished the atropine-blockable component of the response. Peripheral corticosterone replacement of adrenalectomized fa/fa rats restored the hyperinsulinemia. Chronic infusion of dexamethasone intracerebroventricularly to adrenalectomized fa/fa rats increased basal insulin and the secretory response to glucose and this effect was blocked by atropine. In contrast, intracerebroventricular infusion of obese rats with corticotropin releasing factor reduced basal and stimulated insulin levels. It is concluded that the hypersecretion of insulin in obese fa/fa rats results, at least in part, from a central glucocorticoid-mediated stimulation of vagal drive to the pancreatic B-cells.

Adrenalectomy↗

PubMed1990

Increased type II glucocorticoid-receptor numbers and glucocorticoid-sensitive enzyme activities in the brain of the obese Zucker rat.

The possibility that the glucocorticoid-dependence of obesity of the obese fa/fa rat reflects on overactivity of glucocorticoids on the brain has been investigated by studies of enzyme activities and glucocorticoid type II (GR) receptors. The activity of 2 glucocorticoid-sensitive enzymes, glycerol-3-phosphate dehydrogenase and glutamine synthetase, were increased in the hippocampus of obese rats. In contrast malate dehydrogenase and pyruvate kinase, glucocorticoid-insensitive enzymes, were normal. Adrenalectomy of obese rats reduced glycerol-3-phosphate dehydrogenase activity to the level of lean rats. Scatchard analysis of [3H]corticosterone binding showed that the number of type II (GR) receptors was increased in the hypothalamus and hippocampus of obese rats but the affinity of these receptors was reduced. The evidence supports the hypothesis of excessive central glucocorticoid activity in the obese rat.

Adrenal Glands↗

PubMed1990

Relationship between uptake of norepinephrine by hypothalamic homogenates and the activity of brown adipose tissue.

It has previously been established that norepinephrine (NE) in the central nervous system is involved in feeding and the development of obesity. The present experiments were carried out to investigate the relationship between the uptake of NE by a crude hypothalamic homogenate and NE-mediated sympathetic activity in interscapular brown adipose tissue (IBAT). Sympathetic nervous system activity was assessed by measuring the binding of the purine nucleotide guanosine-5'-diphosphate (GDP) to mitochondria isolated from IBAT. Four situations known to alter food intake and sympathetic activity, namely, corticotropin releasing factor infusion, adrenalectomy, fenfluramine treatment and obesity due to genetic transmission were studied. In each case, [3H]NE uptake by the hypothalamic preparation and GDP binding to IBAT mitochondria were measured. A highly significant negative correlation between the uptake of NE by hypothalamic homogenates and the binding of GDP to IBAT mitochondria was obtained in both lean and obese animals. These findings are discussed with regard to the regulation of food intake and sympathetic nervous system mediated thermogenesis.

Adipose Tissue, Brown↗