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.

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.

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.

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.

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.