Contrasts between the effects of zinc-a 2 -glycoprotein, a putative b 3/2 -adrenoceptor agonist and the b 3/2 -adrenoceptor agonist BRL35135 in C57Bl/6 (ob/ob) mice Edward T Wargent 1 , Jacqueline F O’Dowd 1 , Mohamed S Zaibi 1 , Dan Gao 2 , Chen Bing 2 , Paul Trayhurn 1,2 , Michael A Cawthorne 1 , Jonathan R S Arch 1 and Claire J Stocker 1 1 Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK 2 Obesity Biology Unit, Institute of Ageing and Chronic Disease, University of Liverpool, Duncan Building, Liverpool L69 3GA, UK Correspondence should be addressed to C J Stocker Email claire.stocker@buckingham.ac.uk Abstract Previous studies by Tisdale et al. have reported that zinc-a 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 b 3 - and possibly b 2 -adrenoceptors. We compared the effects of dosing recombinant human ZAG (100 mg, i.v.) and BRL35135 (0.5 mg/kg, i.p.), which is in rodents a 20-fold selective b 3 - relative to b 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 b 1 -adrenoceptor mRNA levels in white adipose tissue, but only BRL35135 reduced b 2 -adrenoceptor mRNA. Both ZAG and BRL35135 reduced b 1 -adrenoceptor mRNA levels in brown adipose tissue, but neither influenced b 2 -adrenoceptor mRNA, and only BRL35135 increased b 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 b-adrenoceptor gene expression in adipose tissue, but ZAG did not display the thermogenic effects of the b-adrenoceptor agonist, nor did it increase b 3 -adrenoceptor or UCP1 gene expression in brown adipose tissue. ZAG does not behave as a typical b 3/2 -adrenoceptor agonist. Key Words " zinc-a2-glycoprotein " b 3 -adrenoceptor agonist " ob/ob mice " obesity " glucose tolerance " thermogenesis " BRL35135 Journal of Endocrinology (2013) 216, 157–168 Introduction Zinc-a 2 -glycoprotein (ZAG (AZGP1)), which is identical to the previously named lipid-mobilising factor (LMF) (Hirai et al. 1998), is a 40 kDa single-chain polypeptide similar to the class I major histocompatibility complex heavy chain. It is secreted by both brown and white adipocytes (Bing et al. 2010), as well as other cells, and in humans, ZAG Journal of Endocrinology Research E T WARGENT and others ZAG and a b 3 -adrenoceptor agonist in ob/ob mice 216 :2 157–168 http://joe.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JOE-12-0402 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 02/18/2022 09:52:23AM via free access