Biomedical subjects

D A York

Publications and source records attributed to D A York.

At least 37 records · Page 2Linked to original sources

PubMed1998

Preferential fat intake increases adiposity but not body weight in Sprague-Dawley rats.

It is not known whether an inherent preference for dietary fat promotes obesity in animals allowed to self-select the proportions of fat and carbohydrate consumed. To address this question, Sprague-Dawley rats were given a choice between two diets containing either 78% fat (by energy) or 78% carbohydrate; both diets were equicaloric for protein (22%). The entire study lasted 12 weeks. After an adaptation period, macronutrient preferences were determined by measuring 24 h intake of the two diets for 5 days; fat-preferring animals were classified as those that consumed greater than 60% of total energy from the fat/protein source, and carbohydrate-preferring rats as those that consumed less than 40%. Rats with intermediate macronutrient intakes were excluded. Initial body weight was not different between preference groups. Caloric intakes and body weights were then recorded at approximate weekly intervals, and fat depots were weighed at the time of sacrifice. Measures of energy intake and body weight did not differ between the two preference groups over time. In addition, baseline macronutrient preferences remained stable across the study period. Despite similar body weights, mean epididymal fat depot weight was significantly higher in fat-preferring rats than in carbohydrate-preferring rats (12.6 vs. 10.0 g); also, mean inguinal fat depot weight in fat-preferrers was greater although not reliably different compared to carbohydrate-preferring rats (12.9 vs. 10.9 g). Thus, the preferential intake of fat led to a greater deposition of both subcutaneous and visceral fat without an increase in body weight. These data lead us to conclude that the increased fat deposition was due primarily to the ingestion of fat rather than to excess caloric intake.

Adipose Tissue↗

PubMed1998

Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity.

The Differential Display technique has been used to identify differences in mRNA expression in adipose tissue after the introduction of a high fat diet to two strains of rat (OM and S5B/PI) that differ in their susceptibility to develop obesity on this diet. The insulin receptor tyrosine kinase inhibitor protein (fetuin) was shown to be differentially expressed in OM but not S5B/PI rats. This circulating protein may play a role in the development of peripheral insulin resistance associated with high fat diets.

Animals↗

PubMed1998

Macronutrient selection following 2-deoxy-D-glucose and mercaptoacetate administration in rats.

Mercaptoacetate (MA) and 2-deoxy-D-glucose (2-DG), which block fatty acid oxidation and glucose utilization respectively, were injected in rats that were maintained on a macronutrient self-selection diet consisting of separate jars of carbohydrate, protein, and fat. Rats were divided into two groups based on their baseline preference for carbohydrate or fat. MA increased intake of carbohydrate and protein and decreased intake of fat regardless of the rats' baseline preference. 2-DG increased intake of carbohydrate in rats regardless of baseline preference. Protein and fat intakes were not changed after 2-DG administration. If fat was the only macronutrient source available, 2-DG treated rats consumed significantly more fat compared to the saline control, whereas MA treated rats did not. When protein was the only macronutrient source available, both 2-DG and MA treated rats increased protein intake. MA increases the intake of nutrients which can be utilized by peripheral tissues except fat, which is not being oxidized. 2-DG increases the intake of carbohydrate which may be necessary to overcome the central glucoprivation caused by this drug.

Animals↗

PubMed1998

Chronic d-fenfluramine treatment reduces fat intake independent of macronutrient preference.

We investigated the effect of chronic dexfenfluramine (DFEN) treatment on macronutrient selection in a three-choice diet paradigm using Sprague-Dawley rats. Baseline macronutrient intakes were measured for several days before the initiation of treatment. In Experiment 1, daily intraperitoneal injections of DFEN (1.5 mg/kg) or saline were administered 60 min before dark onset for 12 consecutive days and 24 h macronutrient intakes were measured. DFEN significantly reduced absolute fat intake (kcal) by 30% and relative fat intake (% of total energy) by 14% in animals that received dexfenfluramine treatment compared to controls over the 12-day period. Absolute carbohydrate intake was increased 24% compared to controls, but this difference was not significant. These changes in food intake resulted in a 10% lower total energy intake. Upon discontinuation of the drug, fat intake of the DFEN-treated rats rebounded to control levels within 24 h. In Experiment 2, rats were assigned to carbohydrate- or fat-preferring groups based on the ratio of their average daily carbohydrate to fat intake (kcal). All animals then received DFEN. During DFEN treatment, fat-preferring rats reduced their daily fat intake from 62 to 53% of total energy. The low baseline fat intake of carbohydrate-preferring rats was reduced even further by DFEN (from 24 to 15% of total energy). These corresponding effects of DFEN on macronutrient selection in both fat- and carbohydrate-preferring rats indicate that chronic DFEN treatment selectively suppressed fat intake independent of the preferred macronutrient diet.

Animals↗

PubMed1998

Differential response to kappa-opioidergic agents in dietary fat selection between Osborne-Mendel and S5B/P1 rats.

We have investigated the central effect of a kappa-opioid agonist and an antagonist on the macronutrient preference in two strains of rat, the Osborne Mendel (OM) and S5B/P1 rats, that have different susceptibility to obesity and differential preference for dietary fat intake. OM rats prefer diets high in fat and are sensitive to diet-induced obesity, whereas S5B/P1 prefer a low fat diet and are resistant to high-fat diet-induced obesity. Rats adapted to a two-choice high fat (HF)/low fat (LF) diet were food deprived (20 h) and then infused into the third cerebroventricle with 10 micrograms nor-binaltorphimine (nor-BNI), a selective kappa-antagonist. Nor-BNI preferentially suppressed HF intake, but not LF intake in OM rats, whereas it affected neither diet in S5B rats. Infusion of U50488, a selective kappa-agonist (33 nmol), into the third cerebroventricle in sated rats, potently stimulated the intake of HF only in the OM rats, whereas it induced a significant but moderate stimulation of intake of both HF and LF diets in the S5B/P1 rats. Total energy intake following U50488 was not significantly different between the two strains. These findings suggest that the enhanced sensitivity of the OM rats to kappa-opioid stimulation for dietary fat may contribute to their preference for dietary fat and possibly their increased susceptibility for obesity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Beta-casomorphins stimulate and enterostatin inhibits the intake of dietary fat in rats.

The effects of beta-casomorphins 1-7, 1-5 and 1-4 on food intake of rats adapted to either a high fat (HF) or high carbohydrate (HC) diet have been studied and compared to the effects of enterostatin. Intracerebroventricular (icv) beta-casomorphin1-7 (beta-CM1-7) stimulated intake of HF diet in overnight fasted rats, but beta-CM1-5 and beta-CM1-4 were ineffective. Peripheral injection of beta-CM1-7 also increased the intake of a high fat diet, but reduced the intake of HC diet in satiated rats. Intracerebroventricular (ICV) beta-CM1-7 caused a dose-dependent increase in the intake of HF diet, but a dose-dependent inhibition of HC ingestion in satiated rats. Enterostatin (ICV) inhibited the beta-CM1-7 stimulation of HF intake, as did the general opioid antagonist naloxone. Ligand binding studies with [3H-pro] enterostatin identified on low affinity binding site (Kd 100nM) on a crude brain membrane preparation. This binding was displaced by beta-CM1-7, beta-CM1-5 and beta-CM1-4. These data suggest that at high doses enterostatin and beta-CM1-7 may interact with the same low affinity receptor to modulate intake of dietary fat.

Amino Acid Sequence↗

PubMed1998

Changes in the microstructure of feeding after administration of enterostatin into the paraventricular nucleus and the amygdala.

The effects of enterostatin (ENT) injected into the paraventricular nucleus (PVN) and the amygdala (AMYG) on the microstructure of feeding was studied by using an automated feeding apparatus. In rats adapted to a 6-h meal feeding regime, ENT reduced the size and duration of the first meal after injection in both the PVN and the AMYG. Similar effects were observed when ENT was given at the beginning of the dark cycle in rats fed ad libitum although the onset of feeding was also delayed in this situation. The number of meals and the size of subsequent meals was unaffected by ENT but the eating rate within the first meal was reduced after ENT injection into the AMYG of meal-fed rats. Enterostatin injected into the AMYG at a dose that suppressed feeding did not produce a conditioned taste aversion. ENT given centrally therefore appears to reduce food intake by delaying the initiation of feeding and/or advancing meal termination suggesting that it affects both appetite and satiation mechanisms.

Amygdala↗

PubMed1998

Inhibition of insulin release by enterostatin.

OBJECTIVE: These studies were designed to investigate the mechanism through which enterostatin inhibits insulin secretion from pancreatic islets. DESIGN: A static islet incubation method was used to study the effects of enterostatin on insulin secretion induced by various secretagogues and to investigate the effect of calcium ions and 8-Br-cyclic AMP on the response to enterostatin. Measurements of islet cAMP concentrations in response to enterostatin were also made. RESULTS: Enterostatin (10(-9) to 10(-5) M) inhibited insulin secretion from islets incubated in the presence of 16.7 mM glucose in a dose-dependent manner. Enterostatin also inhibited insulin secretion stimulated by glybenclamide (5.0 and 10 microM), phorbol 12-myristate-13-acetate (TPA) (50 and 100 nM), and the kappa-opioid agonist U50,488 (100 nM). The inhibitory effect of enterostatin on TPA-induced insulin secretion was attenuated but still remained in the absence of extracellular Ca2+. The enterostatin inhibition of insulin secretion was blocked by 8-Br-cAMP (1 mM) independent of extracellular Ca2+. Enterostatin reduced the increase in intracellular cyclic AMP (cAMP) content produced by U50,488 (100 nM) and the changes in cAMP content were parallel with changes in insulin release. CONCLUSION: Enterostatin may suppress insulin secretion through the reduction of cAMP, but other mechanisms may also be possible.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

The effects of a high fat diet on leptin mRNA, serum leptin and the response to leptin are not altered in a rat strain susceptible to high fat diet-induced obesity.

Osborne-Mendel (OM) and S5B/Pl rats differ in their sensitivity to develop obesity when fed a high fat (HF) diet; OM rats become obese, whereas S5B/Pl rats remain thin. We have investigated the possibilities that either an impaired leptin response or resistance to leptin action underlies the sensitivity to this form of obesity in OM rats. In Experiment 1, OM and S5B/Pl rats fed a nonpurified diet were killed at d 0 or were fed either a HF (56% fat energy) or a low fat (LF, 10% fat energy) diet for 2 or 7 d. The HF diet increased serum leptin significantly by d 2 to levels that were similar in both rat strains. At 7 d, leptin levels were lower than at d 2 but remained higher than levels in the d 0 control groups. The leptin mRNA:18S RNA ratio in epididymal adipose tissue increased to higher levels in HF-fed OM rats than in S5B/Pl rats fed that diet. However, although the LF diet had no effect in S5B/Pl rats, it increased leptin mRNA levels in epididymal adipose tissue of OM rats compared with the controls fed the nonpurified diet. In Experiment 2, OM and S5B/Pl rats were fed HF or LF diets for 5 wk. At that time, their feeding response to a range of leptin doses (0, 1, 5 or 10 microgram) given intracerebroventricularly was tested after overnight food deprivation. There was a similar dose-dependent reduction in energy intake in response to leptin in both OM and S5B/Pl rats. These responses were independent of the diet. The data suggest that the susceptibility of OM rats to HF diet-induced obesity is not related to either a loss of central sensitivity to leptin or a failure to enhance leptin production acutely, although the failure to maintain chronically increased levels of serum leptin could contribute to the obesity.

Adipose Tissue↗

PubMed1998

Amygdaloid-lesion hyperphagia: impaired response to caloric challenges and altered macronutrient selection.

Lesions of the most posterodorsal aspects of the amygdala in female rats result in hyperphagia and moderate obesity. In the present study, rats with amygdaloid lesions did not increase their daily food intake when their powdered diet was diluted with 25 or 50% nonnutritive bulk. Control animals adjusted their food intake appropriately. In a second study, rats with lesions ate less food (lab chow pellets) than controls when allowed to eat for only 1 h/day for 10 days. In experiment 3, rats were offered a three-choice macronutrient diet. Whereas four of six control animals preferred the high-fat diet, all eight of the rats with amygdaloid lesions displayed a distinct preference for the high-carbohydrate diet, including those that had preferred the high-fat diet before surgery. These results, along with the previous finding that identical lesions result in hyperinsulinemia, indicate that the amygdala is involved in both the homeostatic regulation of food (caloric) intake and the selection of macronutrients.

Amygdala↗

PubMed1998

Chronic ingestion of dietary fat is a prerequisite for inhibition of feeding by enterostatin.

Enterostatin (Ent), the activation pentapeptide from procolipase, inhibits the intake of dietary fat. The selectivity of the response to fat suggests that the rat must recognize a permissive signal related to dietary fat for the Ent biological response. To investigate the nature of this signal, we studied the effects of Ent in rats that were adapted to either a high-fat (HF) or high-carbohydrate/low-fat (HC) diet and then naively exposed to either HF or HC diets. Ent (1 nmol) was injected into the lateral ventricle of overnight-fasted rats, and food intake was measured. Rats adapted to HF diet and tested with HC diet responded to Ent, but rats adapted to HC diet and tested with HF did not respond to Ent. The groups were maintained on their new test diets for up to 21 days and tested again for their response to Ent at 3, 7, 14, and 21 days. Ent response did not appear in HC-adapted rats switched to HF diet before 21 days. Conversely, the HF-adapted rats, which responded to Ent when tested with HC diet for the first time, did not respond at any subsequent testing time. The data suggest that chronic ingestion of dietary fat is required for Ent action and that chronic consumption of fat initiates a postingestion metabolic, endocrine, or neurochemical change that is required for the biological response to Ent.

Acclimatization↗

PubMed1998

Effects of leptin on insulin secretion from isolated rat pancreatic islets.

Leptin is a hormone secreted by adipocytes as a peripheral metabolic signal for the central regulation of energy homeostasis or the reproductive system. Recent studies demonstrated that leptin receptor mRNA is expressed in pancreatic islets of rodents and that leptin at relatively high doses inhibits glucose-induced insulin secretion from rat islets. However, the physiological mechanism of leptin on insulin secretion has not been identified. In this study, we report that leptin inhibits glucose-induced insulin secretion at lower concentrations ranging from 25 to 50 ng/ml using a static incubation method. A perifusion study revealed that leptin (50 ng/ml) affected the second phase of insulin secretion but not the first phase. Leptin did not affect insulin secretion stimulated by glibenclamide (1 and 5 micromol/l) or forskolin (1 micromol/l). Leptin (50 ng/ml) significantly inhibited insulin secretion induced by the phorbol ester phorbol 12-myristate 13-acetate (TPA) in the presence of Ca2+ but not in the absence of Ca2+. Because TPA is known to activate protein kinase C (PKC), these present results suggest that leptin, at a physiological concentration, suppresses the second phase of insulin secretion by reducing activity of the Ca2+-dependent PKC isoform.

Animals↗

PubMed1998

The MONA LISA hypothesis in the time of leptin.

The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.

Animals↗

PubMed1997

Comparisons of the effects of enterostatin on food intake and gastric emptying in rats.

The effects of central and peripheral administration of enterostatin (ENT) on food intake and gastric emptying of a non-nutrient liquid meal have been studied in rats. Intraperitoneal and intragastric administration of ENT at a dose of 120 nmol suppressed the intake of a high-fat diet but failed to inhibit gastric emptying in Sprague-Dawley (SD) rats. Intracerebroventricular (i.c.v.) ENT (1 nmol) reduced intake of a high-fate diet in Osborne-Mendel (OM) and SD rats but not in S5B/Pl rats, whereas it decreased gastric emptying in S5B/P1 and SD rats but not in OM rats. The data suggest that although central ENT may reduce gastric emptying rate, this effect is not related to the inhibitory effect of ENT on food intake.

Animals↗

PubMed1997

Differences in binding of hepatic nuclear proteins from lean and obese rats to the 5'-upstream region of tyrosine aminotransferase.

The glucocorticoid effects on liver tyrosine aminotransferase mRNA levels have been studied in young, lean, and obese Zucker (fa/fa) rats and 5'-upstream regions of the tyrosine aminotransferase (TAT) gene have been used in gel retardation studies to investigate nuclear protein binding. Hepatic TAT mRNA levels were increased in obese fa/fa rats but were normalized seven days after adrenalectomy. Corticosterone replacement to adrenalectomized rats restored the increased levels of TAT mRNA in the obese animals. A 60-bp fragment of upstream TAT DNA (-2463 to -2403) was identified which showed higher levels of band shifting after incubation with hepatic nuclear proteins of obese rats compared with the proteins from lean animals. This differential level of gel retardation was substantially reduced by alkaline phosphatase treatment of nuclear proteins. Gel retardation was reduced when nuclear proteins were prepared from adrenalectomized obese rats, and increased with nuclear proteins from adrenalectomized rats replaced with corticosterone. DNA affinity chromatography and gel electrophoresis identified three proteins of approximately 58, 62, and 65 kDa in the DNA-protein complex. Increased amounts of these three proteins were purified from nuclei of obese rats. HNF3 alpha antibodies induced hypershift of the gel retardation pattern implicating HNF3 alpha as one of the proteins that binds to the 60 bp DNA fragment. The data support the hypothesis that decreased phosphorylation of nuclear proteins in obese rats is glucocorticoid-dependent and may contribute to the altered transcriptional activity of glucocorticoid-responsive genes.

Adrenalectomy↗

PubMed1997

Feeding response to mercaptoacetate in Osborne-Mendel and S5B/PL rats.

The purpose of this experiment was to determine if Osborne-Mendel (OM) rats, which are susceptible to dietary-induced obesity, and S5B/PL (S5B) rats, which are resistant to dietary-induced obesity, differ in their feeding responses to mercaptoacetate (MA), which blocks fatty acid oxidation, or 2-deoxy-D-glucose (2DG), which blocks glucose utilization. 2DG (100 mg/kg or 200 mg/kg) increased food intake in both strains of rats on a high-fat diet (56% energy from fat). Mercaptoacetate (600 mumol/kg) increased food intake in OM but not S5B rats on a high-fat diet. When maintained on a low-fat diet (10% energy from fat), MA (400 mumol/kg or 600 mumol/kg) stimulated food intake in OM rats, whereas S5B rats increased food intake only after the highest dose of MA (600 mumol/kg). MA stimulated carbohydrate and protein intake in OM rats maintained on a macronutrient selection diet, whereas S5B rats maintained on this diet did not significantly increase intake of any macronutrient after MA. These results demonstrate that OM and S5B rats have a similar food intake response to 2DG but a dissimilar response to MA. The variable response to MA in these strains may be due to a difference in peripheral or central signaling systems related to fatty acid oxidation or a difference in metabolic environments between the strains, which in turn affects the feeding response to MA. These studies suggest that a difference in control of fatty acid oxidation may account for the difference in susceptibility to obesity when eating a high-fat diet.

Animals↗

PubMed1997

Differential effects of baseline macronutrient preferences on macronutrient selection after galanin, NPY, and an overnight fast.

Rats display individual patterns of fat and carbohydrate intakes when allowed to self-select among individual macronutrient diets. We investigated whether these individual preferences in macronutrient selection could be modified by an overnight fast or by two orexigenic peptides, galanin and neuropeptide Y (NPY), which may selectively stimulate fat and carbohydrate intake. Rats were grouped by preference based on the ratio of average baseline fat:carbohydrate intake. In counterbalanced tests conducted on separate days, saline, galanin, or NPY was infused into the paraventricular nucleus of the hypothalamus and 60-min food intake was measured. When the macronutrient intakes were expressed as percent of total caloric intake, galanin administered into the PVN did not increase fat consumption compared to saline injection in either preference group. NPY slightly enhanced the proportion of carbohydrate intake, but only in carbohydrate-preferring rats. When all three feeding stimuli were compared to baseline preferences, the only condition that significantly altered macronutrient selection was an overnight fast, which augmented fat intake. These data demonstrate that baseline preferences for fat or carbohydrate are not significantly modified by galanin or NPY but that an overnight fast increases fat preference.

Analysis of Variance↗

PubMed1997

Effect of enterostatin and kappa-opioids on macronutrient selection and consumption.

Enterostatin, the activation peptide of pancreatic procolipase, suppresses consumption of high-fat diets and selectively suppresses fat consumption over carbohydrate consumption. Kappa-opioid subtype agonists stimulate feeding whereas antagonists suppress feeding. We investigated the effects of enterostatin, the kappa-opioid agonist U50488, and the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) on macronutrient selection and food consumption in rats adapted to choose between a high-fat (HF) diet or a low-fat-high-carbohydrate (LF) diet. In fasted rats, lateral cerebro-ventricular injection (LV) of enterostatin selectively suppressed consumption of the HF diet, with no effect on LF diet consumption. Nor-BNI also selectively suppressed consumption of the HF diet without affecting LF diet consumption. Additionally, U50488 prevented the suppression of consumption of the HF diet in response to enterostatin. In food-sated rates, U50488 preferentially increased consumption of the HF diet and had no effect on consumption of the LF diet. Combined infusions of subthreshold doses of enterostatin and nor-BNI also inhibited consumption of the HF but not the LF diet, whereas combined infusions of maximal doses of enterostatin and nor-BNI had no additive effects. Collectively, these data suggest that a kappa-opioid pathway modulates selection and consumption of diets high in fat and that enterostatin modulates consumption of dietary fat by interacting with this pathway.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗