Overproduction of zinc-α2-glycoprotein by adipose tissue is crucial in accounting for the lipolysis occurring in
cancer cachexia of certain malignant
tumors. The main aim of this study was to explore whether
thyroid hormone could enhance zinc-α2-glycoprotein production in adipose tissue. In addition, the regulation of zinc-α2-glycoprotein by
thyroid hormone in the liver was investigated. We performed in vitro (HepG2 cells and primary human adipocytes) and in vivo (C57BL6/mice) experiments addressed to examine the effect of
thyroid hormone on zinc-α2-glycoprotein production (
mRNA and
protein levels) in liver and visceral adipose tissue. We also measured the zinc-α2-glycoprotein serum levels in a cohort of patients before and after controlling their
hyperthyroidism. Our results showed that
thyroid hormone up-regulates zinc-α2-glycoprotein production in HepG2 cells in a dose-dependent manner. In addition, the zinc-α2-glycoprotein proximal promoter contains functional
thyroid hormone receptor binding sites that respond to
thyroid hormone treatment in
luciferase reporter gene assays in HepG2 cells. Furthermore, zinc-α2-glycoprotein induced lipolysis in HepG2 in a dose-dependent manner. Our in vivo experiments in mice confirmed the up-regulation of zinc-α2-glycoprotein induced by
thyroid hormone in the liver, thus leading to a significant increase in zinc-α2-glycoprotein circulating levels. However,
thyroid hormone did not regulate zinc-α2-glycoprotein production in either human or mouse adipocytes. Finally, in patients with
hyperthyroidism a significant reduction of zinc-α2-glycoprotein serum levels was detected
after treatment but was unrelated to
body weight changes. We conclude that
thyroid hormone up-regulates the production of zinc-α2-glycoprotein in the liver but not in the adipose tissue. The neutral effect of
thyroid hormones on zinc-α2-glycoprotein expression in adipose tissue could be the reason why zinc-α2-glycoprotein is not related to
weight loss in
hyperthyroidism.