Downregulation of zinc-α2-glycoprotein in adipose tissue and liver of obese ob/ob mice and by tumour necrosis factor-α in adipocytes

Abstract

Zinc-α2-glycoprotein (ZAG, also listed as AZGP1 in the MGI Database), a lipid-mobilising factor, has recently been suggested as a potential candidate in the modulation of body weight. We investigated the effect of increased adiposity on ZAG expression in adipose tissue and the liver and on plasma levels in obese (ob/ob) mice compared with lean siblings. The study also examined the effect of the pro-inflammatory cytokine tumour necrosis factor-α (TNFα) on ZAG expression in adipocytes. Zag mRNA levels were significantly reduced in subcutaneous (fourfold) and epididymal (eightfold) fat of ob/ob mice. Consistently, ZAG protein content was decreased in both fat depots of ob/ob mice. In the liver of obese animals, steatosis was accompanied by the fall of both Zag mRNA (twofold) and ZAG protein content (2·5-fold). Plasma ZAG levels were also decreased in obese mice. In addition, Zag mRNA was reduced in epididymal (fivefold) and retroperitoneal (fivefold) adipose tissue of obese (fa/fa) Zucker rats. In contrast to Zag expression, Tnfα mRNA levels were elevated in adipose tissue (twofold) and the liver (2·5-fold) of ob/ob mice. Treatment with TNFα reduced Zag gene expression in differentiated adipocytes, and this inhibition was chronic, occurring at 24 and 48 h following TNFα treatment. It is concluded that ZAG synthesis in adipose tissue and the liver is downregulated, as are its circulating levels, in ob/ob mice. The reduced ZAG production may advance the susceptibility to lipid accumulation in these tissues in obesity, and this could be at least in part attributable to the inhibitory effect of TNFα.

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

“…Endotoxin-free recombinant human ZAG was synthesised by EzBiolab (Carmel, CA, USA) using established methodology (Mracek et al 2010b). Briefly, full-length human ZAG cDNA in the pcDNA 3.2 vector (Invitrogen) was transfected into HEK-293 cells.…”

Obesity, inflammation, and insulin resistance

“…Moreover, this response is recovered by PPARβ/δ agonists, suggesting that inhibition of NF-κB by these drugs can avoid metabolic dysfunction in obese individuals (Serrano-Marco et al, 2012). Another effect attributed to TNF-α is reduced production of zinc α-2 glycoprotein (ZAG), a protein modulating body weight, which hydrolyzes TAG via hormone sensitive lipase (HSL), contributing to increased lipid droplets in WAT and ectopic accumulation in the liver and other peripheral tissues (Rolli et al, 2007;Mracek et al, 2010).…”

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

“…ZAG mRNA and protein expression in adipose tissue (both epididymal and subcutaneous) and the liver are reduced in obese ob/ob mice. 51 In obese Zucker rats, ZAG mRNA levels in epididymal and retroperirenal adipose tissue are decreased too. 51 Similar to the findings in genetic models of obesity, a decrease in adipose tissue ZAG mRNA and serum ZAG levels has been reported in mice, in which obesity is induced by a high-fat diet.…”

“…51 In obese Zucker rats, ZAG mRNA levels in epididymal and retroperirenal adipose tissue are decreased too. 51 Similar to the findings in genetic models of obesity, a decrease in adipose tissue ZAG mRNA and serum ZAG levels has been reported in mice, in which obesity is induced by a high-fat diet. 52 In human subjects, using a gene profiling approach ZAG transcripts have been reported to be decreased in subcutaneous fat of obese women.…”