Studies on catecholamine function in human fat cells

Abstract

Human adipose tissue is a heterogeneous organ as regards metabolism. The effects of catecholamines, the main lipolytic hormones in man vary considerably in different regions. Fat cell lipolysis also changes in a number of physiological and pathophysiological states. The aim of the present study was to focus on two factors of importance for the action of catecholamines on lipolysis in vitro - namely, the influence of heredity and catabolism. The well-known enhancement in the number of beta-adrenoreceptors (beta-AR) in abdominal fat as compared to gluteal fat, may be explained by an increased transcription of the genes coding for beta1- and beta2-AR in the abdominal region. Lipolytic sensitivity to isoprenaline a non-selective beta-AR agonist, varied 106-fold and showed a bimodal distribution in 65 healthy subjects of normal weight. This suggests two populations, one with a high and one with a low isoprenaline sensitivity.

Subjects with a low sensitivity were resistant to the lipolytic action of noradrenaline and the beta2-AR agonist terbutaline. They further displayed a 50% reduction in the in vivo lipolytic response to exercise and mental stress, despite a 50% increase in plasma noradrenaline and a 3-fold increase in plasma adrenaline levels. The lipolytic catecholamine resistance was explained by a reduction in the number of beta2-AR, in turn the result of decreased transcription of the beta2-gene. Another defect in lipolysis activation was found in healthy subjects of normal weight with a heredity for obesity. They showed a 50% reduction in the maximum lipolytic response to catecholamines and also when lipolysis was stimulated with other drugs acting on both proximal and distal steps in the lipolytic cascade. This may have been due to a decrease in the activity of hormone-sensitive lipase (HSL), the enzyme that regulates the last and rate-limiting step in lipolysis.

In obese subjects during four weeks of treatment with a very low-calorie diet (VLCD) lipolysis increased, mainly because of an increase in the basal lipolysis rate, whereas the signalling through the lipolytic cascade remained unchanged on the adrenoceptor and the post- receptor levels. This state was associated with resistance to the antilipolytic and the lipogenic effects of insulin. There was a marked interindividual difference in weight reduction, in spite of satisfactory compliance by all subjects. The sensitivity to the alpha2-adrenoceptor (a2-AR) was thought to be of value for predicting the rate of weight loss during VLCD. In another study of patients with thyrotoxicosis, another catabolic state with high energy expenditure, an increase in catecholamine action was found as regards both lipolytic sensitivity aDd responsiveness. The former was due to a selective upregulation of the number of beta2-AR and the latter was explained by a distal change in the lipolytic chain at the level of the protein- kinase A-HSL complex.

In summary, this study has demonstrated that the regional variation in the number of human beta1- and beta2-AR in adipose tissue is regulated by transcription. Lipolytic resistance to catecholamines may occur in otherwise healthy subjects because of a decreased expression of beta2-AR on both the protein and the mRNA levels or to a decreased activity of HSL. Both these lipolytic abnormalities are observed in the so-called metabolic syndrome, which may mean that the defects are early disturbances in the development of this disorder. Finally, lipolysis adapts to various catabolic states by different mechanisms. Lipid mobilization during caloric restriction is mainly due to an increased basal lipolysis rate and resistance to insulin action, whereas in thyrotoxicosis it is accompanied by an increased catecholamine sensitivity and response due to increased expression of beta2-AR and increased function of HSL. Constitutional variations in a2-AR function may predict weight loss during caloric restriction.