Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Abstract

Objectives:The goal of the current study is to determine whether the -adrenoreceptor (-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-2-glycoprotein (ZAG). Material and Methods:This has been investigated in CHO-K1 cells transfected with the human 1-, 2-, 3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranonol.Results: ZAG bound to the 3-AR with higher affinity (Kd 46+1nM) than the 2-AR (Kd 71+3nM) while there was no binding to the 1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various -AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of 3-AR in gastrocnemius muscle, and in white and brown adipose tissue, but had no effect on expression of 1-and 2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, was completely attenuated by the non-specific -AR antagonist propranolol. Conclusion:The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a -3AR, or possibly a 2-AR.

Contrasts between the effects of zinc-α2-glycoprotein, a putative β3/2-adrenoceptor agonist and the β3/2-adrenoceptor agonist BRL35135 in C57Bl/6 (ob/ob) mice

“…Russell et al ( , 2004 have presented evidence that ZAG is a b 3 -adrenoceptor agonist. Recently, these workers have suggested that ZAG is also a b 2 -adrenoceptor agonist (Russell & Tisdale 2012a). One important property In vivo lipolysis assay following administration of ZAG or BRL35135.…”

“…Some of this evidence involves the use of a high concentration of a marginally selective b 3 -adrenoceptor antagonist (Manara et al 1996, Arch 2011b; however, it is unclear why neither a b 3 -adrenoceptor agonist nor isoprenaline corrected decreased lipolysis in adipocytes from ZAG knockout mice (Rolli et al 2007). One criticism -that ZAG is equally effective as a lipolytic agent in human and rodent white adipocytes despite the b 3 -adrenoceptor playing at best a minor role in human white adipocytes -has recently been countered by a report that ZAG is also a b 2 -adrenoceptor agonist but not a b 1 -adrenoceptor agonist (Russell & Tisdale 2012a). Treatment of 3T3-L1 adipocytes with b 3 -adrenoceptor agonists increases ZAG mRNA expression (Bing et al 2004), opening the possibility that ZAG might mediate the metabolic effects of b 3 -adrenoceptor agonists.…”

“…Animal procedures were conducted in accordance with the University of Buckingham project licence under the UK Animals (Scientific Procedures) Act (1986) (Russell & Tisdale 2010a,b, 2011, 2012a, while that of BRL35135 has been used by a number of workers, including ourselves (Cawthorne et al 1992, Virtanen et al 1997, Bing et al 1998. Food and water intakes for each cage of two mice were measured daily at 0900 h and body weight of each mouse was measured every 3 days.…”

“…In rodents, both b 3 -adrenoceptor agonists and ZAG stimulate lipolysis, increase the expression of uncoupling protein-1 (UCP1) in brown adipose tissue and increase core temperature, suggestive of increased energy expenditure (Granneman et al 2003, Inokuma et al 2006, Russell & Tisdale 2010a, 2011, 2012a. b 3 -Adrenoceptor agonists have not been developed for the treatment of metabolic disease in humans, partly because the b 3 -adrenoceptor is less dominant in human adipose tissue, especially white adipose tissue, than in rodent adipose tissue, and there is less brown adipose tissue in humans than in rodents (Arch 2011a).…”

Effect of curcumin on visfatin and zinc-α2-glycoprotein in a rat model of non-alcoholic fatty liver disease

“…Zinc-α2-glycoprotein (ZAG) can regulate the activity of lipid metabolic enzymes, and hence maintain the balance of lipid metabolism to play a protective role in the pathogenesis of NAFLD [6][7][8] .…”