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Biomedical subjects

G A Bray

Publications and source records attributed to G A Bray.

At least 217 records · Page 12Linked to original sources
PubMed1992

A retrospective view of obesity.

To gain a perspective on 'obesity in the nineties' requires an understanding of where the field came from during the 1980s. Three main themes seem to characterize much of the research during the 1980s. First there was completion of development of multi-disciplinary treatment programmes utilizing the best behavioural modification, nutrition education, exercise and on occasion pharmacological adjuncts. Most characteristic of all was the widespread use of very low calorie diets which first appeared at the beginning of the decade and peaked at its end. The second major development of the 1980s was the recognition of the importance of fat distribution in addition to total fat as a risk factor for the consequences of obesity. Finally, the 1980s saw the development of serotonin agents and the initial studies with beta adrenergic agonists for the treatment of obesity based on the concepts of nutrient partitioning and reduced sympathetic activity. As we enter the 1990s, three additional themes appear to be in the ascendancy. The first will be the emphasis on molecular mechanisms as an explanation for the genetic diversity of obesity, including fat distribution. The second will be the focus on strategies for prevention of obesity. The third will be the development of newer and more innovative techniques for treating that obesity which we cannot prevent.

Adipose Tissue↗
PubMed1992

Obesity increases risk for diabetes.

The relationship of obesity to the development of diabetes has been reviewed. Older individuals are more obese and have more diabetes. Both the duration and magnitude of the obesity increase risk of diabetes. Family history of diabetes mellitus is also important in whether obesity leads to diabetes. Abdominal body fat increases the risk of diabetes. These factors help in understanding the reasons why obesity poses such a high risk for developing diabetes mellitus.

Blood Glucose↗
PubMed1992

A randomized double-blind clinical trial of fluoxetine in obese diabetics.

Fluoxetine is an inhibitor of serotonin re-uptake which has been found to produce weight loss in humans and animals. To test the effects of this drug in obese diabetic subjects, 48 male and female, obese type II non-insulin dependent (NIDDM) diabetics who were being treated with insulin were randomized to receive either fluoxetine 60 mg or a placebo once daily in a randomized double-blind fashion for 24 weeks. A four week single-blind placebo lead-in period preceded and a six week single-blind placebo period followed the double-blind treatment period. Subjects performed daily home glucose monitoring and were given instruction in a 1200kcal American Diabetic Association (ADA) diet. Subjects treated with fluoxetine achieved a maximum 8 kg greater weight loss on average than the placebo-treated subjects. At the end of active treatment, fluoxetine-treated subjects had significantly lower glycohaemoglobin levels than the placebo-treated group (9.72 vs. 10.76%, P < 0.05). In addition, fluoxetine-treated subjects showed a greater decrease in total daily insulin dose than placebo-treated subjects (44.5 vs. 20.1% decrease at the end of active treatment, P < 0.05). These results suggest that fluoxetine may be of benefit in the treatment of obese patients with type II non-insulin dependent diabetes mellitus.

Blood Glucose↗
PubMed1991

Enterostatin suppresses food intake following injection into the third ventricle of rats.

The effect on food intake of an activation peptide from pancreatic pro-colipase, called enterostatin, has been studied after parenteral or third ventricular administration. The activation peptide (enterostatin = Val-Pro-Asp-Pro-Arg = VPDPR) reduced food intake when given intraperitoneally. Low doses of this peptide also reduced food intake when given into the third ventricle, but high doses were ineffective. Enterostatin did not modify the stimulatory effects on food intake of clonidine, an alpha 2-adrenergic agonist, suggesting that its anorectic effects are not mediated via the alpha 2-adrenergic system. These data suggest that enterostatin, an activation peptide from pro-colipase, may play a role in producing satiety.

Analysis of Variance↗
PubMed1991

GABA-related feeding control in genetically obese rats.

Feeding in response to glucoprivation induced by 2-deoxy-D-glucose (2-DG) is impaired in genetically obese (Zucker) rats. Muscimol, a GABAA-agonist (0.5 nmol/0.5 microliter in each area) increased food intake in lean rats over 3 h but in fatty rats only at 30 min after infusion into the VMH. Injection of muscimol into the DMH and PVN increased feeding of both phenotypes. Picrotoxin, a non-competitive GABAA-antagonist (0.1 nmol/0.5 microliter) increased food intake after infusion into the LH of both phenotypes and decreased food intake over a 3 h period when infused into the VMH. DMH and PVN of fatty rats. In the lean littermates, picrotoxin was only effective in reducing food intake at 30 min after infusion into the VMH and PVN but not the DMH. The present results suggest that the fatty Zucker rat has a disturbance in the GABA-related regulatory mechanism of feeding behavior in the ventromedial hypothalamus, which may be responsible for the impaired response to glucoprivation found in these rats.

Animals↗
PubMed1991

Nocturnal growth hormone secretion does not affect diurnal variations in arginine and glucose-stimulated insulin secretion.

There is a diurnal variation in insulin secretion, with higher values in the morning (AM) than in the afternoon (PM). This study tested the hypothesis that nocturnal human growth hormone (hGH) secretion might be the mechanism producing this diurnal variation in insulin secretion. Six healthy normal-weight men were studied on four occasions: twice in the early morning (AM) and twice in the afternoon (PM). Oral methscopolamine (Pamine), an anticholinergic agent that blocks hGH release, was administered at bedtime prior to the AM study or before breakfast for the PM study. An index of insulin secretion in all four tests was obtained from measurement of the acute release of insulin in response to two intravenous (IV) boluses of arginine, one given basally and the other given after raising glucose levels to approximately 150 mg/dL above the baseline. Insulin secretion was significantly greater in the morning than in the afternoon in both control and methscopolamine-pretreated subjects. The mean peak hGH was reduced in subjects pretreated with oral methscopolamine. Drug treatment reduced insulin secretion proportionally in the morning and afternoon. These results suggest that the diurnal insulin response to stimulation with arginine during a hyperglycemic clamp persists despite complete suppression of hGH by anticholinergic blockade, and that the diurnal insulin secretion is not caused by sleep- or meal-induced GH secretion.

Adult↗
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

Pancreatic procolipase propeptide, enterostatin, specifically inhibits fat intake.

Pancreatic procolipase is activated by trypsin forming colipase, a cofactor for pancreatic lipase involved in intestinal fat digestion and a pentapeptide named enterostatin. Enterostatin with the sequence Val-Pro-Asp-Pro-Arg (VPDPR) was previously shown to decrease food intake in rats both after peripheral and central injection. In this work enterostatin has been shown to reduce specifically the consumption of a high-fat diet as opposed to a low-fat diet after central injection of Sprague-Dawley rats. After starvation for 18 hours the rats were given a free choice of a low-fat diet (5.2% fat by weight; 14.1% by energy) and a high-fat diet (17.8% fat by weight; 32.8% by energy) in separate containers. After injection of 200 ng of VPDPR into the lateral ventricle, the rats selectively decreased the intake of the high-fat diet by 45% (p less than 0.005), while the intake of the low-fat diet was unaffected compared to saline injection. VPDP after intracerebroventricular injection had totally lost the selective effect on the consumption of a high- fat and a low-fat diet. It is suggested that enterostatin formed during fat digestion from pancreatic procolipase may provide a feed-back signal for the intake of lipid.

Animals↗
PubMed1991

Obesity, a disorder of nutrient partitioning: the MONA LISA hypothesis.

The mechanisms underlying different types of obesity have been gradually clarified. Animal models with hypothalamic, genetic or dietary obesity have been examined with a feedback model. Four common final pathways are involved in this model. One of these final common pathways is the sympathetic nervous system. Most Obesities kNown Are Low In Sympathetic Activity states the MONA LISA Hypothesis. A second common pathway is the endocrine system involving adrenal glucocorticosteroids. The third common pathway is hyperphagia. Although not essential for most obesities, hyperphagia may be essential in animals with injury to the hypothalamic paraventricular nucleus. The final pathway is reduced physical activity. The tonic activity of these systems and their response to changes in the diet affect nutrient partitioning between fat and protein. This framework has been used to review genetic obesity, hypothalamic obesity and dietary obesity.

Animals↗
PubMed1991

Treatment for obesity: a nutrient balance/nutrient partition approach.

This paper examines the treatment of obesity, using a feedback model of nutrient regulation. A feedback model contains afferent signals and a central controller that transduces afferent information into efferent signals that modulate the controlled system. Using this model and the receptor hypothesis for drug action, a variety of current and potential therapeutic approaches are discussed. Among the more promising approaches would be cholecystokinin agonists, small molecules that mimic ketoacids, agonists to corticotropin-releasing hormone, beta-3 agonists, antagonists to opioid peptides, antagonists to neuropeptide Y, glucocorticoid receptor antagonists, and growth hormone agonists. Since a number of mechanisms can influence body fat and nutrient partitioning, it is likely that optimal therapy will involve use of more than one pharmacologic agent.

Absorption↗
PubMed1991

Weight homeostasis.

This review describes a homeostatic model for the regulation of nutrient intake and the control of partitioning between fat and protein storage. With this homeostatic model, the clinical abnormalities of energy storage such as obesity, anorexia nervosa, and cancer cachexia are examined and potential mechanisms suggested.

Animals↗
PubMed1991

Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats.

To investigate the effects of neuropeptide Y (NPY) on sympathetic nerve activity to interscapular brown adipose tissue (IBAT), we injected NPY into the third cerebroventricle (icv), medial preoptic area (MPOA), anterior hypothalamic area (AHA), paraventricular hypothalamic nucleus (PVN), ventromedial hypothalamic nucleus (VMN), and lateral hypothalamic area (LHA) of anesthetized rats. Multiunit discharges from sympathetic nerves to IBAT were recorded electrophysiologically. The icv injection of NPY suppressed sympathetic nerve activity in a dose-dependent manner, followed by a gradual recovery. The microinjection of NPY (25 pmol) unilaterally into the PVN also significantly suppressed the sympathetic nerve activity to IBAT. In contrast, microinjection of NPY into the MPOA significantly increased the sympathetic nerve activity. The injection of saline into either the PVN or MPOA had no significant effect on sympathetic nerve activity. The microinjection of NPY (25 pmol) into the AHA, VMN, or LHA did not change sympathetic nerve activity to IBAT. We conclude that central administration of NPY affects the sympathetic nerve activity to IBAT and that the suppressive effect of NPY, which may act in part through the PVN, is dominant to the stimulatory effect. The result is consistent with the hypothesis that NPY is a neurochemical modulator of the sympathetic nervous system which controls energy expenditure in IBAT.

Adipose Tissue, Brown↗
PubMed1991

Adrenal sympathetic nerve activity in response to hypothalamic injections of 2-deoxy-D-glucose.

Adrenal sympathetic nerve activity after microinfusion of 2-deoxy-D-glucose (2-DG) into various hypothalamic nuclei was investigated in anesthetized rats. Infusion of 2-DG into the ventrolateral portion of the lateral hypothalamic area (LHA) induced a large and long-lasting increase (greater than 60 min) in adrenal nerve activity. In contrast, infusion into the dorsal or medial portion of the LHA tended to produce a small decrease with a return to baseline within approximately 60 min after the end of the infusion. The direct administration of 2-DG into either the paraventricular nucleus or the dorsomedial hypothalamic nucleus produced a strong inhibition of adrenal nerve activity. Infusions into the ventromedial hypothalamic nucleus induced either a decrease of adrenal nerve activity or were without effect. These findings provide evidence that induction of glucoprivation in the hypothalamus with 2-DG can excite or inhibit adrenal nerve activity, depending on the hypothalamic region. These data also indicate that the ventrolateral portion of the LHA plays an important role in the regulation of adrenal catecholamine secretion in response to glucoprivic conditions in the central nervous system.

Adrenal Glands↗
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

Changes in individual plasma free fatty acids in obese females during fasting and refeeding.

In order to determine whether the metabolism of individual free fatty acids is affected by fasting, plasma levels were measured daily in seven obese females during ten days of fasting and four days of refeeding. There was a gradual rise in free fatty acids throughout the fasting period with some variability during the last three days. Free fatty acids remained high during early refeeding followed by a decrease at the end of refeeding. Changes in concentration were most pronounced for oleic (18:1w9) and palmitic (16:0) acids which had the highest initial levels. Expressed as percent change from baseline, oleic, palmitic, and linoleic (18:2w6) acids had similar patterns, while changes were more dramatic for palmitoleic acid (16:1) and less so for stearic acid (18:0) than the others. When expressed as proportion of total free fatty acids, there was very little change in any individual free fatty acid despite the large fluctuations in actual plasma values. It appears that the five major free fatty acids in plasma undergo similar changes during fasting and refeeding, and the palmitic and oleic acids can serve as suitable tracers for metabolic studies.

Adult↗
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↗
PubMed1990

Effects of insulin on hypothalamic monoamine metabolism.

The concentration of monoamines and/or their metabolites has been measured using in vivo microdialysis in the ventromedial and lateral hypothalamus following the parenteral administration of insulin. Similar measurements were made in rats with lateral hypothalamic microdialysis cannulas in which insulin was given but food intake delayed for 6 h. Serum norepinephrine and epinephrine both increased following injection of insulin, and food intake rose after a delay of 30-60 min. Norepinephrine rose in both the ventromedial and lateral hypothalamus with peaks at 60-90 min. 3-Methoxy-4-hydroxy-phenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) increased in the dialysis from the lateral but not the ventromedial hypothalamus. Serotonin was unchanged following the injection of insulin, but its metabolite, 5-hydroxy-3-indole acetic acid (5-HIAA), fell gradually in both areas. In animals which had recovered from the hypoglycemia during the 6 h after insulin injection, but had not been allowed to eat, the concentration of norepinephrine, serotonin, MHPG and 5-HIAA were all increased in the lateral hypothalamus. DOPAC, however, showed no elevation. With the beginning of food ingestion, all monoamines and their metabolites fell to or toward normal within 30-60 mins. These data are consistent with the hypothesis that glucoprivation may involve increased turnover of norepinephrine and serotonin. Changes in DOPAC, however, appear to be related to the 'stress' components rather than the food intake.

3,4-Dihydroxyphenylacetic Acid↗