Metabolic regulation of food intake.
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Animals↗
Biomedical subjects
D A York
Publications and source records attributed to D A York.
Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats.
The effects of RU 486 (mitepristone), an antagonist of type II glucocorticoid receptors (GR), on the development of obesity in young 5-wk-old obese fa/fa rats has been investigated. After 15 days of treatment, body composition of obese RU 486-treated rats was similar to that of lean-vehicle rats. Analysis of body composition changes showed that RU 486 effectively reversed the obesity. It stopped fat deposition in obese rats but increased protein deposition to the level of lean-vehicle rats. RU 486 prevented the development of hyperphagia and reduced gross energetic efficiency in the obese rats but had little effect on lean rats. Brown adipose tissue mitochondrial GDP binding was increased in obese rats but was reduced in lean rats by RU 486 treatment. RU 486 also reduced the elevated activity of hippocampal glycerophosphate dehydrogenase, a glucocorticoid-responsive enzyme, of obese rats to the level of lean rats. The evidence suggests that abnormal activity of glucocorticoid GR receptors or abnormal cellular responsiveness to corticosterone receptor complexes may be important in the development of obesity in the fa/fa rat.
Animals↗
Interaction of intracerebroventricular insulin and glucose in the regulation of the activity of sympathetic efferent nerves to brown adipose tissue in lean and obese Zucker rats.
The effects of injection of insulin and glucose into the third cerebral ventricle on the firing rate of the sympathetic efferent nerves to intercapsular brown adipose tissue was investigated in anaesthetized lean and obese Zucker rats. Injection of insulin resulted in a dose-dependent (70-480 pmol) inhibition of nerve firing rate, whereas in combination with glucose (140 pmol of insulin and 139 nmol of glucose), insulin strongly potentiated the increase in firing rate seen with glucose alone. Although basal levels of nerve firing rates were lower in the obese rat, responses to insulin, glucose, and insulin plus glucose were qualitatively similar to those seen in the lean rat. These results are consistent with the hypothesis that insulin acts in the central nervous system as a physiological signal in the control of thermogenesis after feeding, and that this effector system is intact in the obese rat.
Action Potentials↗
Tumour necrosis factor-alpha and lymphotoxin have opposite effects on sympathetic efferent nerves to brown adipose tissue by direct action in the central nervous system.
Intracerebral injection of recombinant human tumour necrosis factor-alpha (rTNF alpha) decreased, whereas lymphotoxin increased the activity of the sympathetic efferent nerves to interscapular brown adipose tissue (IBAT). The changes in firing rates were accompanied by a significant dose-dependent change in IBAT and rectal temperatures (which were decreased with rTNF alpha and increased with lymphotoxin treatment). These results indicate that rTNF alpha and lymphotoxin act directly in the CNS to modulate the sympathetic outflow to IBAT. The opposite effects of the two peptides also suggest that in the CNS, separate receptor systems exist.
Action Potentials↗
Studies on the sympathetic efferent nerves of brown adipose tissue of lean and obese Zucker rats.
Previous studies have suggested that the sympathetic tone to brown adipose tissue (BAT) is reduced in the genetically obese (fa/fa) rat. The following experiments were designed to examine with electrophysiological techniques the activity of the sympathetic nerve innervating the interscapular BAT. The spontaneous activity of the efferent nerves was reduced in the obese (fa/fa) rat compared with the lean control. The activity of the nerve showed a linear relationship with changes in core temperature in both genotypes. Electrical stimulation of the ventromedial hypothalamus resulted in similar heat increments in BAT temperature for lean and obese, but this was associated with a smaller increase in nerve firing in the obese rat. Intracerebroventricular administration of glucose enhanced the nerve activity, whereas 2-deoxy-D-glucose reduced the nerve activity in both lean and obese rats. These data suggest that the sympathetic tone is suppressed in the genetically obese rat, but the response to temperature and central glucose metabolism is intact.
Action Potentials↗
Interaction of adrenalectomy and fenfluramine treatment on body weight, food intake and brown adipose tissue.
Three experiments have examined the interaction of adrenalectomy and fenfluramine on food intake, body weight and the binding of guanosine-5'-diphosphate (GDP) to interscapular brown adipose tissue (IBAT). In the first experiment, GDP-binding by IBAT mitochondria from adrenalectomized or sham-operated animals was measured for 3 hr after one of 3 doses of fenfluramine. Fenfluramine stimulated GDP-binding at lower doses in the adrenalectomized animals than in the controls. In the first chronic experiment, adrenalectomy prevented the restoration of normal food intake observed 8-10 days after the beginning of fenfluramine treatment. Adrenalectomy also increased weight loss and enhanced GDP binding to mitochondria from IBAT in rats treated with fenfluramine. In the second chronic experiment, the combination of fenfluramine and adrenalectomy led to a progressive weight loss, continuing hypophagia and stimulation of GDP-binding by IBAT, whereas rats treated with fenfluramine alone showed a recovery of food intake at a stabilized but lower body weight. These data are consistent with the hypothesis that adrenalectomy and fenfluramine disable two separate components of the food intake system and that when combined, produce a profound and persisting disturbance in energy or nutrient balance.
Adipose Tissue, Brown↗
The effects of adrenalectomy, corticotropin releasing factor and vasopressin on the sympathetic firing rate of nerves to interscapular brown adipose tissue in the Zucker rat.
The firing rate of the sympathetic efferent nerves to interscapular brown adipose tissue (IBAT) is lower in the obese rat compared with the lean rat. The present experiments show that adrenalectomy has no effect on nerve firing rate in the lean rat and a small but statistically nonsignificant effect in the obese rat. Injection of corticotropin releasing factor (CRF) into the IIIrd ventricle produced a dose dependent increase in the firing rate of the sympathetic nerves to interscapular brown adipose tissue (IBAT) in both lean and obese rats. The basal (unstimulated) level of firing was lower in the obese rat compared with the lean rat and remained significantly below lean values at each dose. The minimum dose of CRF to see an effect (125 ng) and the dose at which maximum effect on nerve firing rate was observed (500 ng) was similar in both genotypes. Injection of adrenocorticotropic hormone (ACTH) had no effect on nerve firing rate to IBAT. Central administration of vasopressin produced a significant increase in sympathetic firing rate to IBAT in both lean and obese rats. The temperature of IBAT was also significantly increased with vasopressin and the duration of the response was longer compared with CRF, but the minimum dose to see an effect was higher (2.5 micrograms). The response to vasopressin was greater in the obese rat compared with the lean rat but the maximum firing rate did not achieve levels observed in lean rats. Chronic infusion of CRF into the IIIrd ventricle of obese rats resulted in a reduction of food intake and body weight gain but IBAT mitochondrial GDP binding was unaltered by the treatment. These data are consistent with the hypothesis that the defect in the obese Zucker rat may be due to a glucocorticoid inhibition of CRF and/or vasopressin action in the CNS.
Adipose Tissue, Brown↗
Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system.
The basic hypothesis of this review is that studies on models of experimental obesity can provide insight into the control systems regulating body nutrient stores in humans. In this homeostatic or feedback approach to analysis of the nutrient control system, we have examined the afferent feedback signals, the central controller, and the efferent control elements regulating the controlled system of nutrient intake, storage, and oxidation. The mechanisms involved in the beginning and ending of single meals must clearly be related to the long-term changes in fat stores, although this relationship is far from clear. Changes in total nutrient storage in adipose tissue can arise as a consequence of changes in the quantity of nutrients ingested in one form or another or a decrease in the utilization of the ingested nutrients. A change in energy intake can be effected by increased size of individual meals, increased number of meals in a 24-hour period, or a combination of these events. Similarly, a decrease in utilization of these nutrients can develop through changes in resting metabolic energy expenditure which are associated with one of more of the biological cycles such as protein metabolism, triglyceride for glycogen synthesis and breakdown, or maintenance of ionic gradients for Na+ + K+ across cell walls. In addition, differences in energy expenditure related to the thermogenesis of eating or to the level of physical activity may account for differences in nutrient utilization.
Animals↗
Corticosteroid inhibition of thermogenesis in obese animals.
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Adipose Tissue, Brown↗
A study of GDP binding to purified thermogenin protein from brown adipose tissue.
1. The binding of GDP to purified thermogenin protein was studied by using fluorescence spectroscopy and equilibrium dialysis. 2. GDP binding to thermogenin diminished fluorescence emission in a concentration-dependent manner that exhibited saturation. 3. Kd values for binding of nucleoside di- and tri-phosphates were lower than those for nucleoside monophosphates. 4. The GDP-induced fluorescence quenching was decreased by increasing pH, but the apparent Kd was unaltered by pH changes. 5. Equilibrium dialysis showed a Kd change from 3 to 6 microM when the pH was increased from 6.6 to 8.5. 6. The apparent pK of the fluorescence changes induced by pH (8.3) was identical with the apparent pK of the GDP-binding response. 7. The data are consistent with the existence of protonated and non-protonated forms of thermogenin protein that both bind GDP.
Adipose Tissue, Brown↗
Alpha 1- and beta-adrenergic receptors in brown adipose tissue of lean (Fa/?) and obese (fa/fa) Zucker rats. Effects of cold-acclimation, sucrose feeding and adrenalectomy.
1. The populations of alpha 1- and beta-adrenergic receptors in brown adipose tissue (BAT) of genetically obese Zucker rats (fa/fa) were studied with [3H]prazosin and [3H]CGP-12177 respectively. 2. The density of alpha 1-adrenergic receptors in BAT was significantly lower in obese than in lean Zucker rats, both at 2-4 months of age and at 6 weeks of age. The density of beta-adrenergic receptors was identical in BAT of lean and obese 6-week-old Zucker rats. 3. Cold-acclimation increased the alpha 1-receptor density significantly in BAT of both lean and obese Zucker rats, and the number of beta-receptors was also somewhat increased. 4. Sucrose feeding did not affect the density of alpha 1-receptors in BAT of lean or obese Zucker rats, but it increased beta-receptor density. 5. Adrenalectomy restored the density of alpha 1-adrenergic receptors in BAT of obese Zucker rats to the value observed in lean rats. 6. It is concluded that there is a direct correlation between alpha 1-receptor density and tissue recruitment, and that alpha 1-receptor density is thus positively correlated with sympathetic activity. beta-Receptor density is apparently better correlated with feeding conditions.
Adipose Tissue, Brown↗
Regulation of GDP binding and uncoupling-protein concentration in brown-adipose-tissue mitochondria. The effects of cold-acclimation, warm-reacclimation and noradrenaline.
We have used a specific immunoassay for uncoupling protein and [3H]GDP binding to study the acute and chronic responses of brown-adipose-tissue (BAT) mitochondria of warm-acclimated rats to housing at 4 degrees C and cold-acclimated rats to housing at 27 degrees C. These studies have shown the following. (1) In the cold-exposed rat the increase in mitochondrial uncoupling-protein concentration parallels the increase in GDP binding from 1 day to 5 days, but that acutely (initial 4 h) the increase in GDP binding is not associated with any change in uncoupling-protein concentration. 2. In the cold-acclimated rat rehoused at 27 degrees C, GDP binding fell by over 50% in the first 2 days, without any change in uncoupling-protein concentrations. 3. Noradrenaline acutely (30 min) increased BAT mitochondrial GDP binding of lean and obese Zucker rats, without any change in uncoupling-protein concentrations. 4. The increases in GDP binding in cold-exposed rats were associated with increases in the rate of swelling of mitochondria in the presence of valinomycin and potassium acetate. The evidence supports the hypothesis that the acute response of the rat to changes in environmental temperature are associated with unmasking or remasking of uncoupling protein, whereas chronically changes in uncoupling-protein concentration predominate.
Adaptation, Physiological↗
Response of brown adipose tissue to electrical stimulation of hypothalamic centres in intact and adrenalectomized Zucker rats.
Electrical stimulation of the ventromedial nucleus of the hypothalamus (VMN) increased brown adipose tissue (BAT) temperature in lean and obese Zucker rats, whereas stimulation of the paraventricular nucleus (PVN) was without effect in either genotype, before or after adrenalectomy. The prolonged duration of the increase in BAT temperature in the obese (fa/fa) rat observed after VMN stimulation was normalized after adrenalectomy.
Adipose Tissue, Brown↗
Effect of lateral hypothalamic lesion on brown adipose tissue of Zucker lean and obese rats.
Acute (10-day) lateral hypothalamic (LH) lesion induced a reduction of food intake in both lean and obese Zucker rats which averaged about 50% over the course of the first 10 days. The aphagia associated with a fall in body weight in both genotypes which was greater than their respective pair-fed controls, indicating a change in energetic efficiency. The reduced level of BAT protein, mitochondria and GDP binding observed in the obese rat was restored after LH lesion, suggesting the reestablishment of a normal sympathetic drive to the tissue. The markedly lower plasma insulin concentration in the LH lesioned obese rat is consistent with a reduction in parasympathetic activity in these animals. Food restriction in the sham lean rat reduced BAT protein content and mitochondrial GDP binding, whereas no such changes were observed in the food restricted obese rat. This demonstrates the insensitivity of the obese rat to dietary signals and may imply that LH lesion restores diet-induced BAT thermogenesis in the obese rat.
Adipose Tissue, Brown↗
Obituary notice, T.G. Taylor (1919-1987).
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History, 20th Century↗
Effect of hypophysectomy on energy balance and brown fat activity in obese Zucker rats.
Hypophysectomy (HYPX) in genetically obese (fa/fa) Zucker rats significantly reduced body weight and energy gains and stimulated energy expenditure (by 34%), the thermic response to food (by 144%), and brown adipose tissue (BAT) mitochondrial GDP-binding capacity (by 190%) compared with pair-fed, sham-operated obese rats. These changes in energy balance in obese HYPX rats were reversed by corticosterone replacement (1 mg/day), but the increased BAT activity was only partly restored to normal. HYPX had only small effects on energy balance in lean Zucker rats compared with pair-fed, sham-operated lean controls but increased the acute thermic response to food and BAT mitochondrial GDP-binding capacity; these effects were inhibited by replacement of HYPX rats with corticosterone. The results suggest that alterations in the hypothalamic-pituitary-adrenal axis play a fundamental role in the development and maintenance of genetic obesity.
Adipose Tissue, Brown↗
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↗
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↗