Type-specific concordance in young diabetic monozygotic twins.
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Adolescent↗
Biomedical subjects
G A Bray
Publications and source records attributed to G A Bray.
Effect of intrahypothalamic hydroxybutyrate on sympathetic firing rate.
Following the microinjection of 3-hydroxybutyrate into either the paraventricular or ventomedial nucleus of the hypothalamus, there was a significant increase in firing rate of the sympathetic nerves to brown adipose tissue, with a peak increase in activity occurring three minutes following the injection. The response in both hypothalamic regions was dose-dependent. When injected into both regions at the same time, the increase in firing rate was additive. These studies suggest that ketone bodies in the central nervous system may activate the sympathetic nervous system.
3-Hydroxybutyric Acid↗
Effect of fenfluramine on sympathetic firing rate.
The effects of acute and chronic treatment with fenfluramine have been explored in two experiments. Three and twenty-four hours following the injection of fenfluramine 20 mg/kg the firing rate of sympathetic efferent nerves to brown adipose tissue was significantly increased compared to sham injected controls. Body weight loss following acute treatment with fenfluramine was significantly greater at three and twenty-four hours than in the vehicle-treated controls. In the chronic experiment animals were treated once daily for 12 days with 20 mg/kg of fenfluramine. There were two control groups. One control group ate ad lib and a second control group was pair fed to maintain body weight comparable to that of the fenfluramine-treated animals. By the twelfth day food intake in the fenfluramine-treated animals had returned to control levels. Sympathetic firing rate after three days of treatment with fenfluramine was significantly higher in the treated animals than in ad lib fed controls. The ad lib fed controls were likewise significantly higher than the vehicle-treated, pair-gained controls. After 12 days of treatment fenfluramine treated animals had sympathetic firing rates which were still slightly but significantly higher than those of the vehicle-treated controls whereas the vehicle-treated, pair-gained animals had a small but significantly reduced firing rate. These data support the hypothesis that fenfluramine can increase peripheral sympathetic activity.
Animals↗
Nicotine increases thermogenesis in brown adipose tissue in rats.
This study has tested the hypothesis that nicotine might increase thermogenesis in rats by activating the sympathetic nervous system which supplies brown adipose tissue. Three hours after a single injection of nicotine, both the turnover of norepinephrine and the binding of the purine nucleotide, guanosine 5'-diphosphate (GDP) to mitochondria from brown adipose tissue were significantly increased. After 11 days of treatment with nicotine, the turnover of norepinephrine and the GDP binding to mitochondria from brown adipose tissue both remained elevated but weight gain was not different. These data are consistent with the hypothesis that nicotine may have part of its effect through changes in thermogenesis involving sympathetic nervous activation of peripheral thermogenic tissues such as brown adipose tissue.
Adipose Tissue, Brown↗
Sympathetic activity following paraventricular injections of glucose and insulin.
The effect of microinjections of glucose and insulin into the paraventricular nucleus (PVN) on sympathetic firing rate has been examined in rats. Following the injection of insulin 144 pmoles, there was a 30% reduction in sympathetic firing rate with a minimum reached 2 minutes following the injection, and recovery to baseline within 4 minutes. Lower doses of insulin were without effect. Following the injection of glucose 138 nmoles, there was a brief 20% increase in sympathetic firing rate which peaked at 1 minute and had returned to control levels by the second minute. This effect of glucose, like that of insulin, was dose-related. When compared with injections of insulin and glucose into the ventromedial hypothalamus, injection of either substance into the PVN showed a smaller and more attenuated response, raising the possibility that the effect of these nutrients injected into the PVN may be through the small quantities which could reach the ventromedial nucleus. These studies are consistent with the hypothesis that the paraventricular nucleus is not the principal modulator of the sympathetic firing rate.
Animals↗
Sympathetic activity following paraventricular or ventromedial hypothalamic lesions in rats.
The present experiment was designed to measure the sympathetic firing rate of nerve filaments to interscapular brown adipose tissue in rats with acute and chronic lesions in the ventromedial hypothalamus or paraventricular nucleus. Female rats received injections of kainic acid into either the paraventricular nucleus or the ventromedial hypothalamus. The sympathetic activity was measured by recording the firing rate of nerve filaments to interscapular brown adipose tissue after mounting the filaments on silver wire electrodes connected to an amplifier and rate meter. In acute experiments performed 30 minutes after the lesion, the basal firing rate was reduced in both groups and was significantly lower in the VMH-lesioned rats than in those with PVN lesions. In the chronic experiment kainic acid was injected into the VMH or PVN and the sympathetic firing rate was measured 7 to 9 days later. Both lesioned groups gained more weight than controls, but the VMH-lesioned rats gained more weight than the PVN-lesioned rats. The basal firing rate of sympathetic nerve filaments in the VMH-lesioned rats was lower than in the other groups. There was no significant difference in the sympathetic activity between PVN-lesioned and control rats. These experiments support the hypothesis that lesions of the ventromedial hypothalamus reduce the sympathetic activity but that lesions in the paraventricular nucleus do not.
Adipose Tissue↗
Effects of repeated weight loss and regain on body composition in obese rats.
To test the hypothesis that repeated loss and gain of weight through dieting will result in increasing fatness, 200-g female Sprague-Dawley rats were castrated and allowed to become obese on a high-fat diet for 6 wk. Two successive periods of severe food restriction (50% maintenance for 28 d and 25% maintenance for 21 d) were each followed by ad libitum refeeding on the high-fat diet until control body weights were attained. Percent body fat was determined indirectly from body density and total-body water at the end of each cycle. Restricted rats gained weight and attained control body weights on ad libitum feeding without overshooting these weights, and percentage body fat was not different from that of controls at the end of either cycle (cycle 1 22.3 +/- 1.7 vs 23.8 +/- 1.7%; cycle 2 19.0 +/- 1.1 vs 21.6 +/- 0.8%). Repeated cycles of weight loss and regain do not produce increased body fatness or decreased rate of weight loss in ovariectomized rats.
Animals↗
Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats.
Corticotropin-releasing factor (CRF) has been administered into the third ventricle of rats in acute and chronic experiments. Following a single 5-micrograms injection of CRF, there was an acute reduction in food intake at 30 and 60 min that was no longer significant at 3 h. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue (IBAT) of 21-h deprived rats was significantly increased 30 min after the acute infusion of 5 micrograms of CRF. Serum corticosterone was elevated in both groups but was significantly higher in the group treated with CRF. Serum glucose was unchanged. During a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle, the treated animals showed a slight, but significant, decrease in food intake but a progressive decline in body weight of 53 g over 7 days. Mitochondrial GDP binding was increased in the ad libitum-fed rats chronically treated with CRF. Serum corticosterone levels, although significantly higher than controls, were lower than following acute administration of CRF. These data show that CRF can acutely reduce food intake and increase sympathetic activity and that chronically it reduces body weight and may increase sympathetic activity without any consistent decrease in food intake.
Adipose Tissue, Brown↗
Effects of food and light on norepinephrine turnover.
To study diurnal differences in norepinephrine turnover, groups of rats were housed in rooms with alternating 12 h light and 12 h dark where half the animals were in a normal light cycle and half were in a reversed light cycle. Norepinephrine turnover was measured in all groups beginning at 1000 by inhibition of tyrosine hydroxylase. When rats are fed ad libitum, the turnover of norepinephrine in interscapular brown adipose tissue and heart was significantly higher in the normal cycle than in the reversed cycle. In addition, there was an interaction between the turnover of norepinephrine and the feeding and lighting schedules. When animals were adapted to eating from 0700 to 1900, the turnover of norepinephrine was somewhat faster when the animals ate in the reversed cycle than when they ate in the normal cycle. Conversely, when the feeding schedule was reversed and animals ate between 1900 and 0700, the turnover of norepinephrine in the absence of food was slightly slower in the animals eating in the reversed cycle than in those eating in the light cycle. This interaction between lighting and food intake observed in both male and female rats was abolished by ventromedial hypothalamic lesions. These data suggest that food intake and lighting conditions interact as controllers of the sympathetic nervous system and that these interactions are modulated by the ventromedial hypothalamus.
Adipose Tissue, Brown↗
Effect of starvation and food intake on sympathetic activity.
These studies have examined the effect of fasting and nutrient loads on sympathetic firing rate in three groups of rats that develop widely divergent degrees of obesity when eating a high-fat diet. Starvation of Sprague-Dawley rats for 24 or 48 h was associated with a decrease in basal sympathetic activity of nearly 25% in the first 24 h and of slightly greater than 30% in 48 h. This decline in sympathetic activity paralleled the loss of body weight and reduction in adipose tissue mass. After starvation for 48 h, Osborne-Mendel rats, which readily develop obesity when eating a high-fat diet, showed a greater decrease in basal sympathetic activity than did the diet-resistant S 5B/P1 rats. A single liquid 36-kcal intragastric meal was associated with an acute 30% increase in sympathetic firing rate in the overnight-fasted Sprague-Dawley rats. The values 3 h after the meal had returned halfway to normal, and by 6 h they were more than 85% of the way to normal. An intravenous injection of glucose produced a greater rise in sympathetic activity in diet-resistant S 5B/P1 rats than in the diet-sensitive Osborne-Mendel rats. These data are consistent with the hypotheses that sympathetic activity is positively related to nutrient status, that it varies between strains of rats, and that it can be acutely increased by an intragastric meal or by intravenous glucose.
Adipose Tissue↗
Lateral hypothalamus and sympathetic firing rate.
Measurements of sympathetic firing rate have been made after the acute microinjection of glucose or insulin into the lateral hypothalamic area as well as after ablation of this area with locally injected gold thioglucose. Injection of glucose into the lateral hypothalamus (LH) produced a small but significant and dose-dependent reduction in the firing rate of efferent sympathetic nerves to interscapular brown adipose tissue. Injection of insulin into the same region produced a very short-lived increase in efferent sympathetic firing rate. Bilateral lesions in the lateral hypothalamus produced by microinjection and gold thioglucose lowered body weight more than sham injections into the LH of control animals. There was an increase in basal sympathetic firing rate at 3, 9, and 24 h after LH lesions. There was also an increase in firing rate at 1 and 3 days, but by 7 days firing rate had returned to control levels. The data support the hypothesis that LH lesions enhance sympathetic activity but show only very limited modulation by glucose or insulin.
Adipose Tissue, Brown↗
Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity.
We examined the effect of dietary fat on the response to 3-hydroxybutyrate (3-OHB) and insulin infused chronically into the third ventricle in three strains of rats with differing susceptibility to obesity induced by a high-fat diet: Osborne-Mendel rats are most susceptible; Sprague-Dawley-rats are intermediate; and S 5B/Pl rats are most resistant. Ten days after implantation of cannulas into the third ventricle, rats were fed either a low-fat diet or a high-fat diet for 14 days. On day 7, osmotic minipumps were attached to the ventricular cannulas. 3-OHB infusions (3.6 mumol/24 h) reduced food intake and body weight in Sprague-Dawley and Osborne-Mendel rats eating either diet. The dietary fat-resistant S 5B/Pl rats did not respond to the intracerebroventricular infusion of 3-OHB. The infusion of insulin (10 mU/24 h) lowered food intake and body weight in animals eating the low-fat (high-carbohydrate) diet but not in animals eating the high-fat diet. Diet profoundly affects the response to intracerebroventricular infusions of insulin but is without effect on the response to 3-OHB.
3-Hydroxybutyric Acid↗
Diurnal changes in sympathetic activity. Relation to food intake and to insulin injected into the ventromedial or suprachiasmatic nucleus.
The present study was designed to test whether there are diurnal changes in the firing rate of sympathetic nerves to brown adipose tissue and whether these diurnal rhythms influenced the response to insulin injected into the suprachiasmatic nucleus or ventromedial hypothalamic nucleus (VMH). Food intake was highest at the beginning of the dark period (1800-2200 hours) and lowest during the daylight hours (0600-1000 and 1200-1600 hours). The basal sympathetic firing rate was highest at noon (1000-1200 hours) when food intake was lowest. At midnight, when food intake was highest, sympathetic firing rate was lowest. Injection of insulin (77, 144, and 288 pmol) into the VMH produced a dose-dependent depression of sympathetic firing rate at each of the four measurement periods (0400-0600 hours, 1000-1200 hours, 1600-1800 hours, and 2200-2400 hours), but the magnitude of the effect was greater at noon than at night. In contrast, insulin injections into the suprachiasmatic nucleus decreased the sympathetic firing rate at noon but produced a significant increase in the sympathetic firing rate at night. These data show that a diurnal rhythm exists for the sympathetic firing rate. The decrease in firing rate in response to insulin when injected into the VMH is in the same direction but varies in magnitude throughout the day, whereas the responsiveness of the suprachiasmatic nucleus to injections of insulin shows a reversal of response in relation to day/night cycles. The highly significant inverse relationship between basal sympathetic firing rate and food intake suggests that sympathetic activity may be part of an important control system for energy balance.
Action Potentials↗
Obesity. Part I--Pathogenesis.
Obesity--defined by a body mass index above 30 kg per m2--is a major problem for affluent nations. Its prevalence is higher in North America than in Europe--between 9% and 12% of the population. Reduced energy expenditure from exercise or metabolism or both may be an important contributory factor in the development of obesity because of a failure to reduce food intake sufficiently to maintain energy balance. A high ratio of abdominal circumference relative to gluteal circumference carries a twofold or greater risk of heart attack, stroke, hypertension, diabetes mellitus, gallbladder disease, and death. The effect of increased quantities of abdominal fat is greater than that of a similar increase in total body fat on the risks of ill health associated with obesity. Genetic factors appear to contribute about 25% to its etiology.
Adult↗
Obesity. Part II--Treatment.
Conventional diets and increased exercise are the cornerstones of traditional therapy for obesity, but available data suggest that the most important component of any program is the associated behavior modification through which new ways of dealing with old problems can be learned and continually applied. This combined with very-low-calorie diets--less than 800 kcal per day--are in wide use, mostly under medical supervision. The currently available appetite-suppressing drugs are of limited efficacy, but many new ones are under active development and hold promise for the future. The most effective surgical intervention appears to be the gastric bypass operation, but this should be reserved for those who are at high risk from their obesity.
Female↗
Sympathetic activity and food intake of rats with ventromedial hypothalamic lesions.
Following ventromedial hypothalamic lesions, food intake increased from 60 to slightly more than 77 kcal/day during the first 6 days. Body weight increased and sympathetic activity, as measured by the electrical firing rate of efferent nerves to interscapular brown adipose tissue, decreased significantly. During a 6-day period of intragastric overfeeding in which animals with hypothalamic lesions received 60 kcal for the first day and 80 kcal for the remaining 5 days, the VMH-lesioned animals gained significantly more weight than the intact, sham-lesioned controls. This difference in weight gain was paralleled by the increased weight of liver and white adipose tissue. The lesioned animals showed a highly significant reduction in sympathetic activity compared to the normal or slightly increased values observed in the sham-lesioned animals. These studies are consistent with the hypothesis that food-induced increases in sympathetic activity are modulated by the ventromedial hypothalamus.
Animals↗
Lateral hypothalamic lesions and activity of the sympathetic nervous system.
The firing rate of efferent sympathetic nerves to brown adipose tissue was measured on 18 h or 18 d following lateral hypothalamic lesions (LH). Eighteen hours following acute lateral hypothalamic lesions, sympathetic firing rate was significantly increased. Following chronic LH lesions there was a decrease in food intake and a fall in body weight which had stabilized by four days. Eleven days after surgery a group of control animals were food restricted and subsequently pair fed twice daily to maintain a body weight comparable to that of the LH lesioned animals. Food intake was lower in the pair-gained animals on all but one day of the experiment. When studied 18 days following LH lesions, sympathetic firing rates were significantly higher than in either the ad lib or pair-fed controls. Sympathetic firing rate in pair fed rats, on the other hand, was significantly lower than in the sham lesioned rats. These data are consistent with the hypothesis that the LH lesion removes an inhibitory control over sympathetic firing rate both acutely and in chronically lesioned animals and that this increased sympathetic firing rate may play an important role in the maintenance of a lower body weight.
Adipose Tissue, Brown↗