Adrenergic control of human adipose tissue lipolysis

I n normal man, adipose tissueamounts to about 1&20 kg. and thus constitutes the major energy reserve of the body. Fatty acids and glycerol, to which the fatty acids are linked, are the major constituents of the intracellular triglyceride droplet of the fat cell. The fatty acids are mainly assimilated from the plasma triglycerides during periods of dietary excess and released when needed by the body during periods of starvation, physical exercise, etc. Since most major organs of the body, except the central nervous system, can utilize the fatty acids, the release of this important fuel will spare the glucose stores and, as an extension, prevent excessivedegradation of body protein as necessary substrate to form glucose in the liver. Degradation. or lipolysis, of the adipose triglyceride to form fatty acids and glycerol is under precise neural and humoral control. The most important hormones acutely regulating adipose tissue lipolysis in adult man are the neural and circulating catecholamines. Consequently, during periods of raised catecholamine release, lipolysis is greatly increased and the blood levels of fatty acids elevated. The fundamental importance of catecholamines in regulating lipolysis is evident by the fact that administration of /? -adrenergic blocking agents will greatly reduce the fatty acid levels during different lipolytic conditions such as fasting, exercise and following hypoglycaemia [I]. The lipolytic stimulatory effect of endogenous catecholamines is mediated by their /? -receptor stimulating property. The hormone-receptor complex in turn activates adenylate cyclase [2] leading to increased levels of cyclic AMP (CAMP) which, via intermediate steps, leads to phosphorylation and activation of the lipolytic enzyme, hormone-sensitive triglyceride lipase. The cAMP formed is degraded by the enzyme phosphodiesterase (PDE). Although cAMP is an important mediator of adrenergic lipolysis, it seems likely that other, non-cAMP dependent processes may also influence lipolysis. At present, however, the importance of such alternate pathways has not been established. The number of intermediate steps required for the stimulation of lipolysis indicate that the responsiveness and/or sensitivity to catecholamines may be regulated at different levels. Since adipocytes are highly sensitive to catecholamines, these cells are currently being used not only to elucidate the regulation of lipolysis per se. but also to study the basic mode of action of these hormones. Present evidence suggests that the main regulating steps are in the early activation of lipolysis and include: ( I ) degree of stimula0014-2972/80/ 1000-0343502.00 C 1980 Blackwell Scientific Publications tion of rrelative to /&receptors, ( 2 ) affinity of the stimulating agents for PIor Pz-receptors, (3) altered number of P-receptors. (4) altered coupling of the hormone-&receptor complex to activate the adenylate cyclase, and ( 5 ) altered degradation of cAMP by changed phosphodiesterase activity. (1) Endogenous catecholamines have not only /j-agonist properties but may also stimulate z-receptors as pointed out in the paper by Kather el al. [3] in this issue. r-receptor stimulation inhibits adenylate cyclase activation and may, unopposed by concornitant /? -stimulation, lower the cAMP levels. In this way the overall metabolic responsiveness to catecholamines may depend not only on the regulation of the /j-receptor mediated effects, as further discussed below, but also on the degree of stimulation of the r-receptors. Under most normal conditions, however, the concomitant stimulation by catecholamines of inhibitory a-receptors seems to be of minor importance for overall lipolytic regulation. I n the study by Kather el al. [3], r-receptor mediated inhibition of adenylate cyclase is only seen in the presence of a /&blocking agent where the r-stimulation is unopposed. Increased z-receptor stimulation. and erect, by catecholarnines have been reported in hypothyroidism [4]. during prolonged starvation and poorly controlled diabetes, [5 ] . and also in certain subcutaneous regions of the adipose tissue [6,7]. The techniques used to investigate altered ato 1-receptor responsiveness have usually been indirect and more direct approaches are needed to elucidate the basic mechanisms involved. For instance, it is unknown if the number of r-receptors is increased in these conditions or if the relative z-receptor preponderance is exerted at the postreceptor level. A changed ato /? -receptor responsiveness to endogenous catecholamines represents an elegant way to regulate adrenergic lipolysis in the conditions mentioned. Unfortunately, little is known about the a-receptors and their biochemical regulation. Since z-receptor stimulation inhibits adenylate cyclase activity, it may be inferred that regulatory sites sensitive to both aand /? -receptor stimulation coexist in the adenylate cyclase complex, as also suggested in this issue [3]. (2) Endogenous catecholamines have not only zand 8-receptor agonist properties but also varying PIand 82-receptor affinities; the former being greater for noradrenaline and the latter being greater for adrenaline. Based on a number of investigations, including direct binding studies [8], it seems quite clear that the 8-receptor in human fat cells may be characterized as PI. However, some lipolytic effect of ,! &timulation has been shown in human fat cells both in oirro [9], and in