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Notes: Summary 1. The adaptation responsible for a four-fold increase in the magnitude of the calorigenic response to catecholamines has been studied in the cold-acclimated rat which serves as a model in which the magnitude of the response can be varied by varying the acclimation temperature. 2. It is not possible to attribute the enhanced calorigenic response to noradrenaline to an increase in the noradrenaline-stimulated adenyl cyclase (the receptor system for noradrenaline) in either brown adipose tissue or skeletal muscle, the principal tissues in which the response occurs, because no increase in the activity of the noradrenaline-stimulated adenyl cyclase occurs in either tissue in cold-acclimated rats in association with the enhanced response to noradrenaline. 3. A transient increase in the total (fluoride-stimulated) adenyl cyclase occurs in brown adipose tissue during the first week of acclimation to cold. The increase takes place in the absence of protein synthesis and is thought to be due to an alteration of the properties of the plasma membrane as a consequence of the intense cold-induced sympathetic stimulation of this tissue. Transient increases in both total (fluoride-stimulated) and catecholamine-stimulated adenyl cyclase have been observed in skeletal muscle during the first week of acclimation to cold, apparently in association with shivering, but are no longer present when acclimation has fully developed. 4. The mitochondria of both red and white skeletal muscle of cold-acclimated rats are shown to be increased in number but decreased in size. The total mitochondrial mass per gram of muscle is not altered (no change in mitochondrial protein or cytochrome oxidase per gram of tissue) but the mitochondria are smaller (less protein and cytochrome oxidase per mitochondrion) and more numerous (more mitochondria per gram of muscle). Mitochondria isolated from the muscle of cold-acclimated rats have normal ADP/O and respiratory control ratios and an increased rate of state 3 and state 4 respiration. The morphologically altered mitochondria thus appear to have normal coupling and control mechanisms yet to differ metabolically in some respect. 5. The turnover of some, but not all, proteins of the skeletal muscle mitochondria and the brown adipose tissue mitochondria is accelerated in the cold-acclimated rat. The morphological alteration appears thus to be associated with an altered metabolism of mitochondrial proteins. 6. Inhibition of mitochondrial protein synthesis by oxytetracycline prevents the change in mitochondrial morphology (the appearance of the smaller and more numerous mitochondria) in muscle during acclimation to cold and causes its reversal if it has already taken place. It also prevents the proliferation of mitochondria in brown adipose tissue and reverses it if it has already occurred. Mitochondrial protein synthesis is therefore necessary for the development and the maintenance of the altered mitochondrial morphology in both skeletal muscle and brown adipose tissue of the cold-acclimated rat. The treatment with oxytetracycline also prevents the development of the enhanced calorigenic response to noradrenaline during acclimation to cold and reverses it if it has already developed. When cold-acclimated rats undergo deacclimation the increased number of mitochondria in muscle diminishes as does the enhancement of the calorigenic response to noradrenaline. It is concluded that the enhancement of the calorigenic response to noradrenaline is closely associated with the alteration of the mitochondria of muscle and brown adipose tissue. 7. Removal of about one third of the total brown adipose tissue showed that this tissue could not be a major site of the enhanced calorigenic response to noradrenaline in cold-acclimated rats. However, the interscapular brown adipose tissue exerted an influence on the capacity of other tissues, presumably skeletal muscle, to maintain an enhanced calorigenic response to noradrenaline. An endocrine function of interscapular brown adipose tissue has been proposed. 8. The detailed biochemical mechanism of the calorigenic response to noradrenaline remains a mystery. However, the four-fold enhancement of the response in cold-acclimated rats is shown to be associated with an alteration in muscle mitochondria which requires mitochondrial protein synthesis and an increased turnover of some mitochondrial proteins. Moreover, it is influenced in an unknown way by the brown adipose tissue. The alteration in function of these altered mitochondria is not revealed by conventional measurements of metabolic functions. The way in which the altered mitochondria permit the muscle to respond to noradrenaline with such a large increase in metabolic rate is still unknown. It is hoped that the observations reported here will provide some clues to its mechanism.