Contrasts between the effects of zinc-α2-glycoprotein, a putative ß3/2-adrenoceptor agonist and the ß3/2-adrenoceptor agonist BRL35135 in C57Bl/6 (ob/ob) mice.

ABSTRACT

Previous studies by Tisdale et al. have reported that zinc-α(2)-glycoprotein (ZAG (AZGP1)) reduces body fat content and improves glucose homeostasis and the plasma lipid profile in Aston (ob/ob) mice. It has been suggested that this might be mediated via agonism of ß(3)- and possibly ß(2)-adrenoceptors. We compared the effects of dosing recombinant human ZAG (100 µg, i.v.) and BRL35135 (0.5 mg/kg, i.p.), which is in rodents a 20-fold selective ß(3)- relative to ß(2)-adrenoceptor agonist, given once daily for 10 days to male C57Bl/6 Lep(ob)/Lep(ob) mice. ZAG, but not BRL35135, reduced food intake. BRL35135, but not ZAG, increased energy expenditure acutely and after sub-chronic administration. Only BRL35135 increased plasma concentrations of glycerol and non-esterified fatty acid. Sub-chronic treatment with both ZAG and BRL35135 reduced fasting blood glucose and improved glucose tolerance, but the plasma insulin concentration 30 min after administration of glucose was lowered only by BRL35135. Both ZAG and BRL35135 reduced ß(1)-adrenoceptor mRNA levels in white adipose tissue, but only BRL35135 reduced ß(2)-adrenoceptor mRNA. Both ZAG and BRL35135 reduced ß(1)-adrenoceptor mRNA levels in brown adipose tissue, but neither influenced ß(2)-adrenoceptor mRNA, and only BRL35135 increased ß(3)-adrenoceptor and uncoupling protein-1 (UCP1) mRNA levels in brown adipose tissue. Thus, ZAG and BRL35135 had similar effects on glycaemic control and shared some effects on ß-adrenoceptor gene expression in adipose tissue, but ZAG did not display the thermogenic effects of the ß-adrenoceptor agonist, nor did it increase ß(3)-adrenoceptor or UCP1 gene expression in brown adipose tissue. ZAG does not behave as a typical ß(3/2)-adrenoceptor agonist.