Anorexia after adrenalectomy in gold thioglucose-treated obese mice.

The effects of adrenalectomy on food intake, weight gain, plasma glucose, and corticosterone levels were investigated in normal untreated controls and gold thioglucose-(GTG) treated hyperphagic obese mice. Adrenalectomy of normal untreated mice was followed by a transient reduction in food intake and body weight with a return, after approximately 7 days, to levels which paralleled those of untreated sham-operated mice. Plasma corticosterone levels were significantly depressed in all untreated adrenalectomized mice. Plasma glucose levels were not affected by adrenalectomy. In sharp contrast to the response of untreated adrenalectomized mice, adrenalectomy of GTG-treated hyperphagic obese mice was followed by a sudden and persistent drop in food intake (anorexia) and body weight. These mice were unable to maintain their body weight. Despite this condition, the mice did not appear to be physically debilitated until a short time (6-12 h) before their death which was preceded by a period of severe hypoglycemia. These findings indicate that the hyperphagia and weight gain of GTG-treated obese mice is dependent on adrenal hormones. The anorexia after adrenalectomy of GTG-treated hyperphagic obese mice may be the result of a direct dependence of central or peripheral structures involved in the regulation of food intake on adrenal hormones. Alternatively, these structures may be affected by the action of metabolites or hormones which arise as a consequence of adrenal insufficiency.

Gold thioglucose-induced hypothalamic damage, hyperphagia, and obesity: dependence on the adrenal gland.

Previous studies from our laboratory suggested that adrenal hormones may participate, directly or indirectly, in the hypothalamic mechanism involved in the regulation of food intake. In the present studies, the effect of adrenalectomy on the development of gold thioglucose (GTG)-induced hyperphagia and obesity in mice was investigated. As expected, damage to the ventromedial hypothalamus by GTG was followed by hyperphagia and obesity. Ablation of the adrenal glands after the administration of GTG prevented the onset and development of hyperphagia and obesity. The administration of cortisone completely restored the hyperphagia and weight gain of GTG-treated adrenalectomized mice. The administration of desoxycorticosterone not only failed to restore the hyperphagia and obesity in these mice but, rather, led to a suppression of food intake, weight loss, and death. It is concluded that 1) GTG-induced hypothalamic hyperphagia and obesity are dependent on adrenal glucocorticoids, and 2) the ability of adrenal glucocorticoids to restore hyperphagia and obesity in hypothalamic lesioned adrenalectomized mice indicates that adrenal glucocorticoids can act on compounds outside of the ventromedial hypothalamus involved in the control of food intake.

Central nervous system control of hyperphagia in hypothalamic obesity: dependence on adrenal glucocorticoids.

Gold thioglucose (GTG)-treated hyperphagic obese mice exhibit a pronounced anorexia upon adrenalectomy which is reversed by the systemic administration of adrenal glucocorticoids. To determine whether the return of hyperphagia was mediated by an action of the hormones on the central nervous system, food intake and body weight were monitored in anorexic GTG-treated obese adrenalectomized mice which received a single intracerebroventricular (icv) injection of very small amounts of adrenal glucocorticoids, including cortisone, corticosterone, and dexamethasone. The responses of untreated controls and adrenalectomized control mice were also studied. To rule out possible systemic effects of icv injections of adrenal glucocorticoids, food intake and body weight were also monitored in similar mice given a single ip injection of the hormones. We found that hyperphagia was restored and weight loss abolished in anorexic GTG-treated obese adrenalectomized mice after a single icv injection of adrenal glucocorticoids; the dose of cortisone required was found to be 1/60th of that previously shown to be needed systemically to restore hyperphagia. A single ip injection of these adrenal hormones in the small amounts given icv failed to induce hyperphagia in these mice. The icv and ip injections of the adrenal glucocorticoids did not significantly affect food intake or body weight of untreated controls and adrenalectomized control mice. These findings indicate that adrenal glucocorticoids act via the central nervous system in restoring hyperphagia in anorexic GTG-treated obese adrenalectomized mice.

Inhibition of thyrotropin- and dibutyryl cyclic AMP-induced secretion of thyroxine and triiodothyronine by catecholamines.

Thyrotropin (TSH), 1 MU/ml and N6, O2'-dibutyryl adenosine 3',5-cyclic monophosphoric acid (dbcAMP) greatly enhanced the release of thyroxine (T4) and triiodothyronine (T3) from mouse thyroids incubated in vitro. L-Epinephrine (E) and L-norepinephrine (NE) strongly inhibited the TSH and dbcAMP-stimulated release of thyroid hormones; L-isoproterenol (IPNE) exerted a relatively weak inhibition. The inhibition by catecholamines was prevented by the alpha-adrenergic blocker, phentolamine; L-propranolol, a beta-adrenergic blocker, had no effect on the inhibition. The TSH-induced release of thyroid hormones was not affected by adrenergic blockers. Epinephrine did not affect the increase in thyroidal cAMP content induced by TSH. These results indicate that catecholamines act by way of an alpha-adrenergic receptor to suppress TSH-stimulated release of thyroid hormones at a point beyond cAMP formation.

The effects of dimethyl sulfoxide on aortic prostacyclin production and serum thromboxane and plasma fibrinogen levels in rabbits fed a normal versus a cholesterol-enriched diet.

Through an unknown mechanism, dimethyl sulfoxide (DMSO) retards atherogenesis in cholesterol-fed rabbits (CFR). We studied the effects on the development of lesions and prostacyclin (PGI2) production in the thoracic aorta and total serum lipid and cholesterol content of the abdominal aortic serum thromboxane (TXB2) and plasma fibrinogen levels in rabbits fed control versus atherogenic diets, with and without DMSO. Without DMSO, PGI2 production was significantly higher in CFR versus control animals (8.65 +/- 1.0 vs 6.38 +/- 0.3 ng/15 min [p less than 0.02]). DMSO did not influence PGI2 production in any of the groups but significantly reduced the number of atheromatous lesions in CFR (78% +/- 9% vs 8% +/- 4% [p less than 0.001]). With DMSO, CFR had a significant reduction in total lipid levels (422 +/- 5 vs 300 +/- 21 mg/gm dry wt [p less than 0.01]) and cholesterol levels (74 +/- 12.8 vs 31.8 +/- 6.4 mg/gm dry wt [p less than 0.01]) compared with control animals. Fibrinogen levels were significantly lower in CFR versus control animals (0.83 +/- 0.07 vs 2.42 +/- 0.13 mg/ml [p less than 0.01]). TXB2 was lower in DMSO plus control versus control animals alone. In conclusion, DMSO does not appear to act through changes in PGI2 or fibrinogen activity. Its effect in lowering TXB2 in CFR suggests an action on platelet function.

Catecholamine inhibition of thyrotropin-induced secretion of thyroxine: mediation by an alpha-adrenergic receptor.

Thyroxine secretion by mouse thyroid gland incubated in vitro was measured. Thyrotropin or dibutyryl cAMP increased thyroxine secretion several-fold. l-Epinephrine and l-norepinephrine strongly inhibited this stimulated release; l-isoproterenol was relatively ineffective. Phentolamine prevented the inhibition by catecholamines of thyroxine release; l-propranolol had no effect. These findings indicate that stimulation of alpha-adrenergic receptors opposes the action of thyrotropin in the regulation of thyroxine secretion.

Anorexia after adrenalectomy in gold thioglucose-treated obese mice: role of adipose tissue mass.

We have previously shown that following adrenalectomy, gold thioglucose (GTG)-treated hyperphagic obese mice exhibit anorexia, weight loss and a pronounced hypoglycemia which leads ultimately to their death. In the present study, we sought to determine whether the increased adipose tissue mass which is characteristic of GTG-treated obese mice exerted a role in the onset and development of anorexia after adrenalectomy. Accordingly, the effects of adrenalectomy on food intake, weight gain, plasma glucose and corticosterone levels were investigated in normal untreated controls, GTG-treated hyperphagic obese mice and GTG-treated non obese mice. The GTG-treated non obese mice were prepared by restricting their daily intake of chow (pair-feeding) to that consumed by normal untreated mice. After adrenalectomy, all mice were allowed free access to food. As expected, all GTG-treated hyperphagic obese mice exhibited anorexia and weight loss following adrenalectomy. In contrast, about half (52%) of the GTG-treated non obese mice exhibited anorexia and weight loss after adrenalectomy. The response of the GTG-treated non obese adrenalectomized mice was not due to differences in adrenal insufficiency since all adrenalectomized mice had blood levels of corticosterone of less than 0.5 microgram%. These findings indicate that whereas the increased adipose tissue mass of the GTG-treated obese mice appears to be associated with an increased incidence of anorexia following adrenalectomy, increased adipose tissue mass alone does not appear to be essential for the occurrence of anorexia.

Inhibition by hypophysectomy of the hyperphagia and obesity following gold thioglucose.

The effect of hypophysectomy in mice previously treated with gold thioglucose (GTG) was studied with respect to changes in food intake and development of obesity. As expected, all mice treated with GTG alone exhibited lesions in the ventromedial hypothalamus (VMH), hyperphagia and obesity. Hypophysectomy of GTG treated mice prevented the appearance of hyperphagia and obesity. Daily administration of the adrenal corticoid, cortisone, completely restored the hyperphagia and obesity in GTG treated hypophysectomized mice. The amounts of cortisone used did not appreciably affect food intake or body weights of normal, hypophysectomized or GTG treated mice. These findings indicate that the hypothalamic hyperphagia and obesity which normally follows the administration of GTG is dependent on a functional pituitary gland. Furthermore, the specific ability of an adrenal corticoid to completely restore the hyperphagia and obesity of GTG treated hypophysectomized mice in the absence of other pituitary factors, suggests that the pituitary adrenal axis serves as an important link in the regulatory mechanism for control of feeding behavior in the mouse.

Adrenalectomy induced anorexia in gold thioglucose-treated obese mice: metabolic and hormonal changes.

Adrenalectomy of gold thioglucose (GTG)-treated hyperphagic obese mice had been shown by us earlier to result in anorexia, weight loss, hypoglycemia and subsequent death of all mice. More recent studies suggest that adipose tissue mass may not be the critical determinant of anorexia since a large proportion of GTG-treated non obese (pair-fed to curb obesity) mice when challenged with adrenalectomy also developed anorexia. The aim of the present studies was to determine whether the changes in circulating metabolites, namely, glucose, free fatty acids and hormones, including insulin, glucagon and ACTH, which accompany adrenalectomy, might provide a clue to the causative agent for the onset of anorexia in GTG obese and non obese mice. Accordingly, plasma levels of glucose, free fatty acids, insulin, glucagon and ACTH were measured in GTG-treated obese, non obese and in normal untreated mice following adrenalectomy or a sham operation. Preoperatively, plasma insulin levels were significantly elevated in GTG obese mice whereas plasma glucose, free fatty acids and glucagon levels were not appreciably different than those of untreated controls. Upon adrenalectomy and onset of anorexia, GTG obese mice exhibited a progressive decline in blood glucose and insulin levels; plasma free fatty acids increased precipitously but only after the first day. Plasma glucagon levels declined immediately following adrenalectomy, however, by the 6th day postoperatively they were significantly elevated above the sham operated obese and untreated controls. Prior to adrenalectomy, the pair-fed GTG non obese mice exhibited blood glucose and insulin levels well below the levels of untreated controls and GTG obese mice whereas plasma free fatty acids and glucagon levels were markedly elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Mediation by serotonin of gold thioglucose-induced necrosis of the ventromedial hypothalamus.

Agents that lower serotonin levels or inhibit serotonin action prevent GTG-indurea and that such damage leads to abnormally increased capillary permeability. Since the VMH is rich in serotonin and since serotonin is a potent oedema-producing agent mice, these findings indicate that the production of necrosis by GTG is mediated by release of serotonin from the damaged pericapillary processes.

Enhancement of experimental atherosclerosis by aspirin.

The effect of aspirin on experimentally induced atherosclerosis was studied in rabbits. Rabbits were placed on an atherogenic diet containing either no aspirin or 0.2% aspirin supplement. Control rabbits were fed regular rabbit food or rabbit food supplemented with 0.2% aspirin. Ingestion of aspirin from the diets containing aspirin was equivalent to a daily dose of 100 mg/kg. As expected, 2 mo after the rabbits were placed on the atherogenic diet, extensive atheromatous lesions were observed on gross examination sporadically distributed along the walls of the aorta. The coronary arteries also exhibited atheromatous lesions on microscopic examination. Addition of aspirin to the atherogenic diet intensified the atherosclerosis as measured by proliferation of the intima of the aorta and coronary arteries and increased occurrence and distribution of atheromatous plaques. It is concluded that, under the conditions of this experiment, the addition of aspirin to an atherogenic diet greatly intensified atherogenesis.

Inhibition of cholesterol-induced atherosclerosis in rabbits by dimethyl sulfoxide.

The effect of dimethyl sulfoxide (DMSO) on cholesterol-induced atherosclerosis in the rabbit was investigated. Two groups of rabbits were studied: a Control group which received regular chow and an Experimental group which received an atherogenic diet containing 1% cholesterol. DMSO was either omitted or added to the drinking water of both groups in amounts of 2, 4, 5 and 6%. After 3 months all animals were autopsied; the thoracic aorta was examined for atheromatous lesions and the abdominal aorta assayed for total cholesterol content. As expected the thoracic aortas of all rabbits in the Control group were free of atheromatous lesions. With the exception of one rabbit in the Experimental group, all rabbits on the atherogenic diet which did not receive DMSO had extensive aortic lesions covering 82 +/- 5% of the surface area of the thoracic aorta. Aortic lesions were inhibited by about 50% in rabbits on 2% (dose, 1.5 g/kg) DMSO and virtually absent in the majority of rabbits on 4 (dose, 3.5 g/kg), 5 (dose, 5.5 g/kg) and 6% (dose, 9.1 g/kg) DMSO. The food intake of rabbits on the atherogenic diet was not suppressed by DMSO. Changes in the cholesterol content of the abdominal aortas paralleled the presence or absence of lesions in the thoracic aorta. Blood cholesterol levels were greatly elevated in all rabbits on the atherogenic diet and not lowered by DMSO. In conclusion, cholesterol induced atherosclerosis in the rabbit was inhibited by DMSO. This action of DMSO was independent of the hypercholesterolemia and not due to a suppression of food intake. DMSO may provide a useful probe for investigating the underlying mechanism(s) in the development of cholesterol induced atherosclerosis.

Cholesterol-induced atherosclerosis in the rabbit: effect of dimethyl sulfoxide on existing lesions.

Earlier studies have established that the analgesic and anti-inflammatory compound, dimethyl sulfoxide (DMSO), was effective in preventing atherosclerosis in cholesterol-fed rabbits. In the present studies, the effect of DMSO on existing atherosclerotic lesions in cholesterol-fed rabbits was investigated. Rabbits were placed on an atherogenic diet containing 1% cholesterol for a period of 10 weeks. At the end of the 10-week period, the rabbits were randomly divided into two groups: one group was placed on a control diet consisting of regular rabbit chow for an additional 12-week period, whereas the remaining group was continued on the atherogenic diet. During this period half of the rabbits in each of these groups were treated with DMSO (approximately 5 g/kg) which was included in their drinking water. Food consumption and fluid intakes were monitored daily and body weights at weekly intervals. Total serum cholesterol levels were measured at periodic intervals. Lipid deposits in the eye which accompany atherosclerosis were examined before and at 12 weeks after institution of the new dietary regimens. At the end of 12 weeks, all rabbits were killed and the thoracic aortas were examined for changes in the extent of atherosclerosis. Food consumption and body weight increased in rabbits on the control diet and in those treated with DMSO. Those maintained on the atherogenic diet showed little change in food intake or body weight. Fluid intake was significantly elevated in all rabbits placed on DMSO. Serum cholesterol levels returned to normal in all rabbits on the control diet. Serum cholesterol levels remained unchanged in rabbits kept on the atherogenic diet alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inhibition of purine enzymes on benzodiazepine binding in the human brain.

Since inosine is an inhibitory ligand for benzodiazepine binding, and since several of the purine enzymes have a specific localization, it was hypothesized that the unique distribution of benzodiazepine receptors may be dependent on the regional concentrations and specific actions of these enzymes in increasing or decreasing the amount of inosine. To test the above theory, the binding of 3H-flunitrazepam to receptors was studied on homogenates of various regions of autopsied human brain before and after treatment with irreversible potent inhibitors of the purine enzymes guanine deaminase and adenosine deaminase. As predicted, inhibition of guanase, which metabolizes guanine and hypoxanthine to xanthine, caused a marked inhibition of binding in the cerebral cortex and midbrain, where there is an abundance of enzyme, and only slight change in binding in the medulla, cerebellum or pons, where there is little enzyme. When adenosine deaminase, which converts adenosine to inosine, was inhibited, there was increased binding, with as much as a 4-fold increase in the frontal lobe, and very little effect in the cerebellum, medulla or temporal lobe.

Gold thioglucose obesity syndrome.

Parenteral administration of gold thioglucose to mice produces an area or necrosis in the ventromedial portion of the hypothalamus. The lesion, like lesions produced by electrocautery of this area, causes hyperphagia and consequent obesity. The glucose moiety of gold thioglucose is essential for production of the lesion. Glucose analogues (2-deoxy-glucose, sodium thioglucose and phlorizin) prevent the gold thioglucose-induced lesion, and by themselves produce a transient hyperphagia. Insulin deficiency prevents the lesion. Either adrenalectomy or hypophysectomy counteracts the effect of insulin deficiency. Electron microscopic studies, in which general necrosis is avoided by administration of aspirin before gold thioglucose or by administration of subnecrotic doses of gold thioglucose, reveal that gold thioglucose primarily affects neural elements contiguous with capillaries in the ventromedial hypothalamus. The experimental observations indicate the presence of special glucoreceptor cells in the ventromedial hypothalamus that are involved in the regulation of food intake.

Biochemical and histopathologic comparison between blood and saline storage of canine veins.

Patency of vein grafts may be influenced by the medium in which they are stored temporarily. We compared saline solution vs blood on prostanoid production and maintenance of endothelium in canine veins after 1 hour of storage at 23 degrees C with 0.2 mg/ml of papaverine. Spontaneous and arachidonate-stimulated prostaglandin levels were measured by radioimmunoassay. Endothelial integrity was analyzed by light and electron microscopy. Prostaglandin production in blood vs that in saline solution was 1821 +/- 1264 and 1259 +/- 719 pg/cm2/min at control and 6705 +/- 3702 vs 6264 +/- 3409 pg/cm2/min, respectively, after stimulation. There were no statistically significant differences between the groups at any time point. Thromboxane levels were also indistinguishable between groups. Microscopy revealed 70% endothelial loss in blood vs 95% for saline solution. We conclude that endothelial preservation is enhanced by blood storage, that the medial layer produces substantial amounts of prostacyclin, and that additional storage solutions need to be investigated.

Action of gold thioglucose on pericapillary structures in the ventromedial hypothalamus.

The administration of GTG to mice leads to death of all structures in a circumscribed area of the VMH as a result of loss of blood circulation. The loss of circulation is due to damage by GTG of neural processes adjacent to some of the capillaries in this area; damage to these processes leads to abnormal capillary permeability. Pericapillary damage occurs under conditions where capillary damage and consequent necrosis are prevented. Abnormal capillary permeability appears to follow release of a vasoactive substance from the damaged neural processes. Damage to the pericapillary neural processes by GTG is insulin-dependent and is counteracted by glucocorticoids.