4 - Catecholamines and intermediary metabolism

Abstract

The sympatho-adrenal system contributes to the regulation of metabolism in a wide variety of physiological and pathophysiological states. The evidence that catecholamines mediate some of the metabolic responses in hypoglycaemia, exercise, cold exposure, and haemorrhagic shock is considerable. In hypoglycaemia catecholamines enhance hepatic glucose output by stimulating glycogenolysis in liver and muscle. Hepatic glycogen breakdown results in immediate glucose delivery into the circulation; glycogenolysis in muscle increases circulating lactate, which may serve as a precursor for glucose synthesis in liver. Mobilization of free fatty acids from triglyceride stores in adipose tissue is mediated by catecholamines as well. In exercise catecholamines increase free fatty acid mobilization from adipose tissue; the role of catecholamines in enhancing hepatic glucose output and increasing muscle lactate is less clear. In acute cold exposure increased free fatty acid mobilization from adipose tissue depends on catecholamines; other metabolic changes are less well defined. In haemorrhagic shock free fatty acid mobilization and muscle lactate production are probably mediated by catecholamines. In all these situations catecholamines result in the suppression of insulin and the stimulation of glucagon; the altered insulin and glucagon levels reinforce the direct effects of catecholamines and provide the proper hormonal milieu for the full expression of the direct effects of catecholamines. The net result is the rapid mobilization of stored fuel, with the production of readily utilizable substrates to meet increased energy requirements. The metabolic adaptation to fasting, however, despite increased glycogenolysis, lipolysis, and gluconeogenesis, along with low insulin and elevated glucagon, is associated with a reduced total energy requirement. The metabolic changes in fasting appear to be independent of catecholamines. The metabolic sequelae of reduced sympatho-adrenal activity in fasting are unknown, except for the possibility that reduced sympathetic activity may contribute to a decrease in heat production and conservation of calories. In cold acclimatization (chronic cold exposure) the increase in sympatho-adrenal activity, although responsible for the increased thermogenesis, is not known to be associated with specific changes in intermediary metabolism. The relative importance, in these diverse states, of circulating epinephrine and of norepinephrine released locally from the sympathetic nerve endings has not been clearly delineated. Circulating epinephrine, if present in high enough concentration, can certainly stimulate glycogenolysis, gluconeogenesis and lipolysis. Hypoglycaemia, however, is the only situation in which epinephrine appears to be preferentially and predominantly secreted. In other situations, epinephrine would appear to reinforce the action of locally released norepinephrine at most sites. There is a reasonable amount of evidence that sympathetic nerves play an important role in the regulation of hepatic metabolism. It seems likely that abrupt changes in hepatic glucose output are initiated by impulses in the sympathetic nerve endings. The sympathetic nerves are probably important in the mobilization of free fatty acids from adipose tissues. There is a suggestion, however, that adipose tissue is non-homogeneous both in its response to sympathetic nerve stimulation and to infusions of catecholamines. Animal experiments suggest that subcutaneous fat is mobilized by stimulation of the sympathetic nerves, whereas mesenteric fat is more resistant. In skeletal muscle, a clear-cut role for sympathetic innervation of the muscle cells, as distinct from the vasculature, has not been established. The metabolic role of catecholamines is twofold. First, both epinephrine and norepinephrine provide for the acute energy needs of the organism by aiding in the rapid breakdown of local fuel stores for the tissue in which these stores are located, and by stimulating the rapid mobilization of the major energy stores in liver, skeletal muscle and fat for consumption in metabolizing tissues throughout the organism. The haemodynamic effects of catecholamines simultaneously serve to distribute the mobilized substrates according to the needs of the various tissues. Second, catecholamines, in conjunction with thyroid hormones, determine the general level of metabolic activity. Thus, in starvation, when the organism's fuel supply is limiting, metabolic activity is decreased in accord with the need for fuel conservation; in cold exposure, exercise and hypoglycaemia, when the energy requirements are great, mobilization of fuel results in an increase in the level of metabolism. In these opposing situations of lesser or greater energy requirements, the activity of the sympatho-adrenal system reflects the ability of the central nervous system to perceive the metabolic needs of the organism and to initiate and sustain an integrated and appropriate response.