Download PDF
Horm Metab Res 2020; 52(10): 755-763
DOI: 10.1055/a-1186-0649
Endocrine Research

Zinc-α2-Glycoprotein Knockout Influenced Genes Expression Profile in Adipose Tissue and Decreased the Lipid Mobilizing After Dexamethasone Treatment in Mice

Wenge Zhang
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
,
Yu Qiao
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
,
Fulei Qi
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
,
Qingyi Shen
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
,
Ruqian Zhao
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
,
Xiaojing Yang
1   MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing, P. R. China
› Author Affiliations Funding Information: This study was supported by the National Natural Science Foundation of China (31772696), the National Key Research and Development Program of China (2016YFD0500502), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Zinc-α2-glycoprotein (ZAG), as an adipokine, plays an important role in lipid metabolism. However, its influence on whole gene expression profile in adipose tissue is not known. Under stress condition, how ZAG affects the lipid metabolism is also unclear. Therefore, in this study ZAG systemic knockout (KO) mice were used as a model to reveal the genes expression profile in visceral fat tissues of ZAG KO mice and wild-type mice by genome-wide microarray screening. Then dexamethasone (DEX) was used to explore the effect of ZAG deletion on body fat metabolism under stress. Our results showed that 179 genes were differentially expressed more than 1.5 times between ZAG KO mice and wild type mice, of which 26 genes were upregulated dramatically and 153 genes were significantly downregulated. Under DEX simulated stress, ZAG systemic knockout in vivo resulted in a markedly decrease of triglycerides (TG) and nonesterified fatty acid (NEFA) content in in plasma. Similarly, for lipid catabolism, ZAG KO led to a significant increase of phosphorylated HSL (p-HSL) protein and a rising tendency of adipose triglyceride lipase (ATGL) protein relative to those of the DEX group. For lipid anabolism, fatty acid synthase (FAS) and adiponectin protein expression in visceral fat rose notably in ZAG KO mice after DEX treatment. In conclusion, ZAG knockout can affect the gene expression profile of adipose tissue, reduce elevated TG and NEFA levels in plasma, and alter lipid metabolism under DEX treatment. These findings provide new insights into the mechanism of lipid metabolic disorders in response to stress.

Key words

ZAG - dexamethasone - lipometabolism - mice


Publication History

Received: 06 January 2020

Accepted after revision: 13 May 2020

Article published online:
15 June 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Burgi W, Schmid K. Preparation and properties of Zn-alpha 2-glycoprotein of normal human plasma. J Biol Chem 1961; 236: 1066-1074
    CrossrefPubMedGoogle Scholar
  • 2 Steinauer A, Larochelle JR, Knox SL. et al. HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins. Proc Natl Acad Sci USA 2019; 116: 512-521
    CrossrefPubMedGoogle Scholar
  • 3 Bao Y, Bing C, Hunter L. et al. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes. FEBS Lett 2005; 579: 41-47
    CrossrefPubMedGoogle Scholar
  • 4 Rolli V, Radosavljevic M, Astier V. et al. Lipolysis is altered in MHC class I zinc-α2-glycoprotein deficient mice. FEBS Lett 2007; 581: 394-400
    CrossrefPubMedGoogle Scholar
  • 5 Bing C, Bao Y, Jenkins J. et al. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc Natl Acad Sci USA 2004; 101: 2500-2505
    CrossrefPubMedGoogle Scholar
  • 6 Russell ST, Tisdale MJ. Studies on the anti-obesity activity of zinc-α2-glycoprotein in the rat. Int J Obesity (2005) 2011; 35: 658-665
    CrossrefPubMedGoogle Scholar
  • 7 Selva DM, Lecube A, Hernández C. et al. Lower Zinc-α2-Glycoprotein production by adipose tissue and liver in obese patients unrelated to insulin resistance. J Clin Endocrinol Metab 2009; 94: 4499-4507
    CrossrefPubMedGoogle Scholar
  • 8 Zulkifli I, Siegel HS, Mashaly MM. et al. Inhibition of adrenal steroidogenesis, neonatal feed restriction, and pituitary-adrenal axis response to subsequent fasting in chickens. Gen Comp Endocrinol 1995; 97: 49-56
    CrossrefPubMedGoogle Scholar
  • 9 Krystyna PK, Marta DW, Peter O. et al. The effect of CRH, Dexamethasone and Naltrexone on the Mu, Delta and Kappa opioid receptor agonist binding in lamb hypothalamic-pituitary-adrenal Axis. Folia Biol (Krakow) 2015; 63: 187-193
    CrossrefPubMedGoogle Scholar
  • 10 Lee RA, Harris CA, Wang JC. Glucocorticoid receptor and adipocyte biology. Nucl Receptor Res 2018; 5: 101373
    PubMedGoogle Scholar
  • 11 Chruvattil R, Banerjee S, Nath S. et al. Dexamethasone alters the appetite regulation via induction of hypothalamic insulin resistance in rat brain. Mol Neurobiol 2016; 54: 7483-7496
    CrossrefPubMedGoogle Scholar
  • 12 Agarwal SK, Marshall GD. Glucocorticoid-Induced Type 1/Type 2 cytokine alterations in humans: A model for stress-related immune dysfunction. J Interferon Cytokine Res 1998; 18: 1059-1068
    CrossrefPubMedGoogle Scholar
  • 13 Bruder ED, Lee PC, Raff H. Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids. J Appl Physiol (1985) 2005; 98: 981-990
    CrossrefPubMedGoogle Scholar
  • 14 Xiao X, Li H, Qi X. et al. Zinc alpha2 glycoprotein alleviates palmitic acid-induced intracellular lipid accumulation in hepatocytes. Mol Cell Endocrinol 2017; 439: 155-164
    CrossrefPubMedGoogle Scholar
  • 15 Xu C, He J, Jiang H. et al. Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol 2009; 23: 1161-1170
    CrossrefPubMedGoogle Scholar
  • 16 Yu CY, Mayba O, Lee JV. et al. Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS One 2010; 5: 15188
    CrossrefPubMedGoogle Scholar
  • 17 Russell ST, Tisdale MJ. Studies on the anti-obesity activity of zinc-alpha2-glycoprotein in the rat. Int J Obes (Lond) 2011; 35: 658-665
    CrossrefPubMedGoogle Scholar
  • 18 Russell ST, Isdale MJ. Role of beta-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-alpha2-glycoprotien (ZAG). Biochim Biophys Acta 2012; 1821: 590-599
    CrossrefPubMedGoogle Scholar
  • 19 Xu MY, Chen R, Yu JX. et al. AZGP1 suppresses epithelial-to-mesenchymal transition and hepatic carcinogenesis by blocking TGFβ1-ERK2 pathways. Cancer Lett 2016; 374: 241-249
    CrossrefPubMedGoogle Scholar
  • 20 Peckett AJ, Wright DC, Riddell MC. The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism 2011; 60: 1500-1510
    CrossrefPubMedGoogle Scholar
  • 21 Jitrapakdee S. Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. Int J Biochem Cell Biol 2012; 44: 33-45
    CrossrefPubMedGoogle Scholar
  • 22 Joëls M. Functional actions of corticosteroids in the hippocampus. Eur J Pharmacol 2008; 583: 312-321
    CrossrefPubMedGoogle Scholar
  • 23 Hinds TD, Sadeesh R, Cash HA. et al. Discovery of glucocorticoid receptor-β in mice with a role in metabolism. Mol Endocrinol 2010; 24: 1715-1727
    CrossrefPubMedGoogle Scholar
  • 24 Xu C, He J, Jiang H. et al. Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol 2009; 23: 1161-1170
    CrossrefPubMedGoogle Scholar
  • 25 Wang Y, Jones Voy B, Urs S. et al. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 2004; 134: 1032-1038
    CrossrefPubMedGoogle Scholar
  • 26 Serr J, Suh Y, Oh SA. et al. Up-regulation of adipose triglyceride lipase and release of non-esterified fatty acids by dexamethasone in chicken adipose tissue. Lipids 2011; 46: 813-820
    CrossrefPubMedGoogle Scholar
  • 27 Hirai K, Hussey HJ, Barber MD. et al. Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients. Cancer Res 1998; 58: 2359-2365
    PubMedGoogle Scholar
  • 28 Cabassi A, Tedeschi S. Zinc-α2-glycoprotein as a marker of fat catabolism in humans. Curr Opin Clin Nutr Metab Care 2013; 16: 267-271
    CrossrefPubMedGoogle Scholar
  • 29 Tedeschi S, Pilotti E, Parenti E. et al. Serum adipokine zinc α2-glycoprotein and lipolysis in cachectic and noncachectic heart failure patients: relationship with neurohormonal and inflammatory biomarkers. Metabolism 2012; 61: 37-42
    CrossrefPubMedGoogle Scholar
  • 30 Wargent ET, O'Dowd JF, Zaibi MS. et al. 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. J Endocrinol 2013; 216: 157-168
    CrossrefPubMedGoogle Scholar
  • 31 Mracek T, Stephens NA, Gao D. et al. Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients. Br J Cancer 2011; 104: 441-447
    CrossrefPubMedGoogle Scholar
  • 32 Russell ST, Tisdale MJ. Studies on the antiobesity effect of zinc-α2-glycoprotein in the ob/ob mouse. Int J Obes (Lond) 2010; 35: 345-354
    CrossrefPubMedGoogle Scholar
  • 33 Russell ST, Tisdale MJ. Role of β-adrenergic receptors in the oral activity of zinc-α2-glycoprotein (ZAG). Endocrinology 2012; 153: 4696-4704
    CrossrefPubMedGoogle Scholar
  • 34 Zhu HJ, Ding HH, Deng JY. et al. Inhibition of preadipocyte differentiation and adipogenesis by zinc-α2-glycoprotein treatment in 3T3-L1 cells. J Diabetes Investig 2013; 4: 252-260
    CrossrefPubMedGoogle Scholar
  • 35 Zimmermann R, Strauss JG, Haemmerle G. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004; 306: 1383-1386
    CrossrefPubMedGoogle Scholar
  • 36 Chakrabarti P, Kim JY, Singh M. et al. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol 2013; 33: 3659-3666
    CrossrefPubMedGoogle Scholar
  • 37 Claus TH, Lowe DB, Liang Y. et al. Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose. J Pharmacol Exp Ther 2005; 315: 1396-1402
    CrossrefPubMedGoogle Scholar
  • 38 Blondin DP, Daoud A, Taylor T. et al. Four-week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue. J Physiol 2017; 595: 2099-2113
    CrossrefPubMedGoogle Scholar
  • 39 Gohda T, Makita Y, Shike T. et al. Identification of epistatic interaction involved in obesity using the KK/Ta mouse as a Type 2 diabetes model: is Zn-alpha2 glycoprotein-1 a candidate gene for obesity?. Diabetes 2003; 52: 2175-2181
    CrossrefPubMedGoogle Scholar
  • 40 Mracek T, Ding Q, Tzanavari T. et al. The adipokine zinc-alpha2-glycoprotein (ZAG) is downregulated with fat mass expansion in obesity. Clin Endocrinol (Oxf) 2010; 72: 334-341
    CrossrefPubMedGoogle Scholar