The overall objective is to study the interrelationships of sympathetic nervous system activity and peripheral thyroid hormone metabolism, as they relate to the metabolic and thermogenic adaptation to altered nutritional states in normal and obese man. Differences in the adaptation of spontaneously obese man to overnutrition may promote excessive weight gain and predisposes these individuals to diabetes mellitus and other diseases. Studies to be performed include measurement of the effect of chronic beta-adrenergic suppression on peripheral thyroid metabolism and energy expenditure during overnutrition in man to determine whether diet-induced changes in norepinephrine (NE) secretion modulate the dietary-induced alterations in resting energy expenditure and thyroxine (T4) deiodination. Measurements of peripheral triiodothyronine (T3) production and energy expenditure during chronic beta-adrenergic stimulation will be made in both lean and obese man during isocaloric diets to determine whether abnormal sensitivity or secretion of NE may impair thyroxine deiodination during overfeeding. The in vitro correlates of changes in nonthyroidal production of T3 will be examined including measurement of beta-adrenergic stimulated hepatic 5'deiodinase activity in lean and spontaneously obese fatty rats (fa/fa). The effect of beta-adrenergic suppression will be studied during overfeeding and carbohydrate refeeding to determine whether suppression of dietary-induced increases in adrenergic tone alter the nonthyroidal production of T3 via changes in enzyme activity. Nonthyroidal production of T3 in man will be measured using a simultaneous pulse tracer injection of I125-T3 and I31-T4 and determination of the metabolic clearance of each hormone. Beta-adrenergic stimulation will be provoked by the administration of terbutaline for 14 days in both lean and obese man. Beta-adrenergic suppression will be performed using propanolol for 14 days. These drugs will also be given to rats in appropriate dosages to stimulate similar responses. Hepatic 5'-deiodinase activity in rats will be performed by measuring the rate of T4 to T3 conversion in liver homogenates before and during various dietary and drug manipulations. The results of these experiments should provide information on abnormal hormonal interactions during the adaptation to altered caloric intake in mammals which may predispose them toward obesity.
