Characterization of ß3-adrenoceptor function in human fat cells

Abstract: Human white adipocytes have, besides ß1- and ß2-adrenoceptors, also been found to express a third ß-adrenergic receptor, termed the ß3-adrenoceptor. The functional role and clinical implications of the ß3-adrenoceptor is however poorly elucidated. The aim of the present study was therefore, first, to study the physiological role of the ß3-adrenoceptor in adipocyte function, i.e. Iipolysis regulation, under both normal and pathologic conditions, second, to search for polymorphisms in the ß3-adrenoceptor gene which might be important for adrenoceptor function and, third, to evaluate the lipolytic effects of new, putative ß3-adrenoceptor selective agonists in human fat cells. CGP12177 (ß1/ß2-antagonist, ß3-agonist) induced a lipolytic response which was correlated to the response induced by noradrenaline, ß1- and ß2-receptor agonists as well as agents acting at the post receptor level, indicating that the ß3-adrenoceptor most likely acts via the adenylate cyclase system. Different antagonistic effects of selective ß1-, ß2- and non-selective ß-antagonists on CGP12177 mediated lipolysis compared to the effects on dobutamine- and terbutaline-induced lipolysis further supported the existence of a third, specific ß3-adrenoceptor in man. In abdominally obese subjects, the rate of FFA and glycerol response to norepinephrine in omental adipocytes was twofold higher as compared to non-obese subjects. In contrast to ß1- and ß2 adrenoceptor function, the ß3-adrenoceptor sensitivity was about 50 times enhanced and the coupling efficiency of the ß3-adrenoceptor was increased from 37 to 56 % in obesity. Furthermore, a 6-fold decrease in alpha2-adrenoceptor sensitivity in obese subjects was also observed. ß1,2,3-adrenoceptor mediated omental fat cell lipolysis was further investigated in subjects representing a wide range of abdominal adipose tissue distribution. A significant difference in ß3 adrenoceptor sensitivity was found between subjects with a high moderate and low WHR. These groups also differed regarding various metabolic parameters and blood pressure. No difference in ßl or ß2-adrenoceptor sensitivity was however found between the WHR subgroups. Only minor regional differences in adrenoceptor lipolytic function was observed in non-obese males. In obese males, the rate of noradrenaline induced glycerol release and noradrenaline sensitivity were 2- and 3-fold higher, respectively, in omental versus subcutaneous fat cells. These findings were accompanied by a 50-fold increase in ß3-adrenoceptor sensitivity, a smaller increase in ß1 adrenoceptor sensitivity, as well as increased ß3- and ß1-lipolytic rates. Three polymorphisms were identified in the ß3-adrenoceptor gene. These were found to be in almost complete association, together constituting two ß3-haplotypes termed ß3-Trp and ß3-Arg. Out of 208 subjects, the ß3-Arg haplotype was more than twice as frequent in obese as in non-obese subjects. No differences in WHR, blood pressure or metabolic parameters were observed between the ß3-Arg and ß3-Trp haplotypes. However, omental adipocyte ß3-adrenoceptor sensitivity was 10-fold decreased in subjects carrying the ß3-Arg haplotype. Among a number of agents with potential interest as anti-obesity drugs, only CL 316 243 and CGP 12177 had selective partial ß3-agonist effects in human omental adipocytes. BRL 37344 and SM 11044 were also partial agonists but displayed significant ß1- and ß2-adrenoceptor agonist properties. ICI D7114 was found to be a non-selective ß-adrenoceptor antagonist. In conclusion, evidence for the existence of a functional ß3-adrenoceptor in human adipocytes has been demonstrated. The lipolytic function of this ß3-adrenoceptor in omental fat cells is increased in obese as compared to non-obese subjects as well as in individuals with signs of the metabolic syndrome. This receptor alteration could contribute to the observed increase in noradrenaline-induced lipolysis in obese subjects, which in turn may promote the delivery of FFA to the portal system and the liver, resulting in the metabolic disturbances observed in upper-body obesity. Furthermore, polymorphisms in the ß3-adrenoceptor gene may be involved in the development of obesity, due to a decreased ß3-adrenoceptor function. Finally, although CL 316 243 has ß3-selective agonist properties in human adipocytes, the potency may be too low for therapeutic use in man.